Certain alkylene diamine-substituted pyrazolo[1,5,-a]-1,5-pyrimidines and pyrazolo [1,5-a]-1,3,5-triazines

ABSTRACT

Disclosed are compounds of the formula:  
                 
 
     where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and X are defined herein. These compounds are selective modulators of NPY1 receptors. These compounds are useful in the treatment of a number of CNS disorders, metabolic disorders, and peripheral disorders, particularly eating disorders and hypertension. Methods of treatment of such disorders and well as packaged pharmaceutical compositions are also provided.  
     Compounds of the invention are also useful as probes for the localization of NPY1 receptors and as standards in assays for NPY1 receptor binding. Methods of using the compounds in receptor localization studies are given.

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims priority from Provisional Application No.60/15869, filed on Sep. 30, 1999, which is incorporated herein byreference.

FIELD OF THE INVENTION

[0002] This invention relates to certain alkylene diamine-substitutedpyrazolo[1,5,-a]-1,5-pyrimidines and pyrazolo [1,5-a]-1,3,5-triazineswhich selectively and potently bind mammalian neuropeptide Y (NPY)receptors. This invention also relates to pharmaceutical compositionscomprising such compounds. It further relates to the use of suchcompounds in treating physiological disorders associated with an excessof neuropeptide Y, especially feeding disorders, some psychiatricdisorders, and certain cardiovascular diseases.

BACKGROUND OF THE INVENTION

[0003] Neuropeptide Y (NPY) is a 36 amino acid peptide first isolated in1982 [K. Tatemoto, M. Carlquist, V. Mutt, Nature, 296, 659, (1982)] andsubsequently found to be largely conserved across species. It belongs toa large family of peptides which includes, among others, peptide YY(PYY) and pancreatic peptide (PP). NPY is the most abundant peptide inthe mammalian brain, but is also localized in sympathetic neurons andNPY-containing fibers have been found in peripheral tissues, such asaround the arteries in the heart, the respiratory tract, thegastrointestinal tract, and the genitourinary tract. Central injectionof NPY elicits a multitude of physiological responses, such asstimulation of feeding, increase in fat storage, elevation of bloodsugar and insulin, anxiolytic behaviors, reduction in locomotoractivity, hormone release, increase in blood pressure, reduction in bodytemperature, and catalepsy. In the, cardiovascular system, NPY isbelieved to be involved in the regulation of coronary tone, while in thegastrointestinal tract, PYY is reported to cause inhibition of gastricacid secretion, pancreatic exocrine secretion, and gastroinestinalmotility. These effects are selectively mediated by various NPYreceptors which currently include the Y₁, Y₂, Y₃, Y₄, and Y₆ subtypes,in addition to the hypothetical Y_(1-like) subtype [C. Wahlestedt, D.Reis, Ann. Rev. Pharmacol. Toxicol., 33, 309 (1993); D. Gehlert, P.Hipskind, Curr. Pharm. Design, 1, 295 (1995); M. C. Michel et al.,Pharmacol. Rev., 50, 143 (1998)]. Selective peptidic agonists andantagonists have been identified for most of the subtypes, but fewselective non-peptidic antagonists have been reported [B. A. Zimanyi, Z.Fathi, G. S. Pointdexter, Curr. Pharm. Design, 4, 349 (1998)]. The Y₁and Y₅ receptor subtypes appear to be involved in appetite regulation,but their relative contribution to the modulation of food intake andenergy expenditure remains unclear [D. R. Gehlert, P. A. Hipskind, Exp.Opin. Invest. Drugs, 6, 1827, (1997)]. The discovery of non-peptidicantagonists of the Y₁ and/or Y₅ receptor, would provide noveltherapeutic agents, devoid of the shortcomings of the peptideantagonists, namely, for example, poor metabolic stability, low oralbioavailability, poor brain permeability, for the treatment of obesityand cardiovascular diseases. Recently, a few of those agents have beenreported [D. R. Gehlert, P. A. Hipskind, Exp. Opin. Invest. Drugs, 6,1827, (1997); P. Hipskind et al., J. Med. Chem., 40, 3712 (1997); M.Muller et al., Arch. Phann. Pharm. Med. Chem., 330, 333 (1997); H.Zarrinmayeh, et al., J. Med. Chem., 41, 2709 (1998); H. A. Wieland etal., Br. J. Pharmacol., 125, 549 (1998); Y. Shigeri et al., Pharmacol.Letters, 63, PL 151 (1998); D. M Zimmerman et al., Bioorg. Med. Chem.Letters, 8, 473, (1998); L. Criscione, J. Clin. Invest., 102, 12, 2136(1998); Y. Murakami, et al., J. Med. Chem., 42, 2621 (1999); T. C.Britton et al., Bioorg. Med. Chem. Letters, 9, 475, (1999); H.Zarrinmayeh, et al., Bioorg. Med. Chem. Letters, 9, 647, (1999)], someof which having demonstrated pharmacological efficacy in pre-clinicalanimal models. The present invention provides a novel class of potentnon-peptidic antagonists of the NPY receptors, in particular, the Y1receptor.

[0004] Insofar as is known, aminoalkyl substitutedpyrazolo[1,5,-a]-1,5-pyrimidines and pyrazolo[1,5-a]-1,3,5-triazineshave not been previously reported as NPY receptor(s) antagonists usefulin the treatment of feeding and cardiovascular disorders. However, thisgeneral class of compounds has been described for other uses by virtueof different mechanisms of action. For instance, WO 98/03510 and WO99/38868 (Du Pont Pharmaceuticals) disclosespyrazolo[1,5,-a]-1,5-pyrimidines and pyrazolo [1,5-a]-1,3,5-triazines asantagonists of the corticotropin releasing factor (CRF). Therein, otherprior art relative to pyrazolo[1,5,-a]-1,5-pyrimidines andpyrazolo[1,5-a]-1,3,5-triazines is also described. Similar compoundshave also been described in WO 97/29109, 98/08847, and D. J. Wustrow etal., Bioorg. Med. Chem. Lett. 8, 2067 (1998).

SUMMARY OF THE INVENTION

[0005] Compounds that interact with the Y₁ receptor and inhibit theactivity of neuropeptide Y at those receptors are useful in treatingphysiological disorders associated with an excess of neuropeptide Y,including eating disorders, such as, for example, obesity and bulimia,and certain cardiovascular diseases, for example, hypertension.

[0006] This invention relates to novel compounds, compositions, andmethods for the treatment of physiological disorders associated with anexcess of neuropeptide Y. The novel compounds encompassed by the presentinvention are those of formula I

[0007] wherein:

[0008] X is N or CR¹⁴;

[0009] R¹ is selected from H, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, (C₃-C₁₀cycloalkyl) C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cyano, halo,C₁-C₆ haloalkyl, OR⁷, C₁-C₆ alkyl-OR⁷; C₁-C₆ cyanoalkyl, NR⁸R⁹, C₁-C₆alkyl-NR⁸R⁹;

[0010] R is H,

[0011] C₁-C₆ alkyl which optionally forms a C₃-C₆ aminocarbocycle or aC₂-C₅ aminoheterocycle with A or B, each optionally substituted at eachoccurrence with R⁷,

[0012] C₃-C₁₀ cycloalkyl, or

[0013] (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl;

[0014] or R2 and R⁶ jointly form with the 2 nitrogen atoms to which theyare bound a C₂-C₅ aminoheterocycle optionally substituted at eachoccurrence with R⁷;

[0015] A is (CH₂)_(m) where m is 1,2 or 3 and is optionally mono- ordi-substituted on each occurrence with C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl,(C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, cyano,halo, C₁-C₆ haloalkyl, OR⁷, C₁-C₆ alkyl-OR⁷; C₁-C₆ cyanoalkyl, NR⁸R⁹,C₁-C₆ alkyl-NR⁸R⁹,

[0016] or A and B jointly form a C₃-C₆ carbocycle, optionallysubstituted at each occurrence with R⁷,

[0017] or, as mentioned above, A and R² jointly form a C₃-C₆aminocarbocycle or a C₂-C₅ aminoheterocycle optionally substituted ateach occurrence with R⁷;

[0018] B is (CH₂)_(n) where n is 1,2 or 3 and is optionally mono- ordi-substituted on each occurrence with C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl,(C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cyano,halo, C₁-C₆ haloalkyl, OR⁷, C₁-C₆ alkyl-OR⁷; C₁-C₆ cyanoalkyl, NR⁸R⁹,C₁-C₆ alkyl-NR⁸R⁹, or, as mentioned above, B and A jointly form a C₃-C₆carbocycle, optionally substituted at each occurrence with R⁷

[0019] or, as mentioned above, B and R² jointly form a C₃-C₆aminocarbocycle or a C₂-C₅ aminoheterocycle optionally substituted ateach occurrence with R⁷;

[0020] R³ is selected from H, C₁-C₆ alkyl, C₃-C₁₀ cycloaakyl, (C₃-C₁₀cycloalkyl) C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cyano, halo,C₁-C₆ haloalkyl, OR⁷, C₁-C₆ alkyl-OR⁷, C₁-C₆ cyanoalkyl, NR⁸R⁹, C₁-C₆alkyl-NR⁸R⁹;

[0021] R⁴ is selected from aryl or heteroaryl, each optionallysubstituted with 1 to 5 substituents independently selected at eachoccurrence from C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl,(C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, halogen,C₁-C₆ haloalkyl, trifluromethylsulfonyl, OR⁷, C₁-C₆ alkyl-OR⁷, NR⁸R⁹,C₁-C₆ alkyl-NR⁸R⁹, CONR⁸R⁹, C₁-C₆ alkyl-CONR⁸R⁹, COOR⁷, C₁-C₆alkyl-COOR⁷, CN, C₁-C₆ alkyl-CN, SO₂NR⁸R⁹, SO₂R⁷, aryl, heteroaryl,heterocycloalkyl, 3-, 4-, or 5-(2-oxo-1,3-oxazolidinyl), with theproviso that at least one of the positions ortho or para to the point ofattachment of the aryl or heteroaryl ring to the pyrazole issubstituted;

[0022] R⁵ is selected from:

[0023] C₁-C₆ alkyl, (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, each of which is substituted with 1 to 5 groupsindependently selected at each occurrence from halo, C₁-C₂ haloalkyl,OR⁷, cyano, NR⁸R⁹, CONR⁸R⁹, COOR⁷, SO₂NR⁸R⁹, SO₂R⁷, NR¹¹COR²,NR¹¹SO₂R⁷;

[0024] C₁-C₆ arylalkyl, C₁-C₆ heteroarylalkyl, C₅-C₈ arylcycloalkyl, orC₅-C₈ heteroarylcycloalkyl, where aryl is phenyl or naphthyl, andheteroaryl is 2-,3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, triazinyl,1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, isoxazolyl, indolyl,pyrazolyl, quinolyl, isoquinolyl, 2-, 4-, or 5-thiazolyl,benzothiadiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl,2-triazinyl, 2-pyrazinyl, 2-, or 3-furanyl, 2-, or 3-thienyl, 2-, or3-benzothienyl, or 1-, 2- or 5-tetrazolyl, each of which is optionallysubstituted with 1 to 5 substituents independently selected at eachoccurrence from C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl,(C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, C₁-C₆ alkenyl, halogen, C₁-C₆haloalkyl, trifluromethylsulfonyl, OR⁷, NR⁸R⁹, C₁-C₆ alkyl-OR⁷, C₁-C₆alkyl-NR⁸R⁹, CONReR⁹, COOR⁷, CN, SO₂NR⁸R⁹, SO₂R⁷, aryl, heteroaryl,heterocycloalkyl, 3-, 4-, or 5-(2-oxo-1,3-oxazolidinyl), with theproviso that 2 adjacent substituents can optionally form together aC₃-C₁₀ cycloalkyl ring, a C₃-C₁₀ cycloalkenyl ring or a heterocycloalkylring;

[0025] C₃-C₁₀ cycloalkyl substituted with 1 to 6 substituentsindependently selected at each occurrence from C₁-C₆ alkyl, C₃-C₁₀cycloalkyl, C₃-C₁₀ cycloalkenyl, (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, C₁-C₆alkenyl, halogen, C₁-C₆ haloalkyl, OR⁷, NR⁸R⁹, with the proviso thatwhen two OR⁷ or NR⁸R⁹ substituents are geminally located on the samecarbon R⁷ is not H and they can form together a C₂-C₄ ketal, oxazoline,oxazolidine, imidazoline, or imidazolidine heterocycle, C₁-C₆ alkyl-OR⁷,C₁-C₆ alkyl-NR⁸R⁹, CONR⁸R⁹, COOR⁷, CN, oxo, hydroximino, C₁-C₆alkoximino, SO₂NR⁸R⁹, SO₂R⁷, heterocycloalkyl, aryl, heteroaryl, wherearyl or heteroaryl is optionally substituted with 1 to 5 substituentsindependently selected at each occurrence from C₁-C₆ alkyl, C₃-C₁₀cycloalkyl, C₃-C₁₀ cycloalkenyl, (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, C₁-C₆alkenyl, halogen, C₁-C₆ haloalkyl, trifluromethylsulfonyl, OR⁷, NR⁸R⁹,C₁-C₆ alkyl-OR⁷, C₁-C₆ alkyl-NR⁸R⁹, CONR⁸R⁹, COOR⁷, CN, SO₂NR⁸R⁹, SO₂R⁷,aryl, heteroaryl, heterocycloalkyl, 3-, 4-, or5-(2-oxo-1,3-oxazolidinyl), with the proviso that 2 adjacentsubstituents can optionally form together a C₃-C₁₀ cycloalkyl ring, aC₃-C₁₀ cycloalkenyl ring or a heterocycloalkyl ring;

[0026] aryl or heteroaryl, optionally substituted with 1 to 5substituents independently selected at each occurrence from halogen,C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl, (C₃-C₁₀ cycloalkyl)C₁-C₆ alkyl, C₁-C₆ alkenyl, halogen, C₁-C₆ haloalkyl,trifluromethylsulfonyl, OR⁷, NR⁸R⁹, C₁-C₆ alkyl-OR⁷, C₁-C₆ alkyl-NR⁸R⁹,CONR⁸R⁹, COOR⁷, CN, SO₂NR⁸R⁹, SO₂R⁷, aryl, heteroaryl, heterocycloalkyl,3-, 4-, or 5-(2-oxo-1,3-oxazolidinyl), with the proviso that 2 adjacentsubstituents can optionally form together a C₃-C₁₀ cycloalkyl ring, aC₃-C₁₀ cycloalkenyl ring or a heterocycloalkyl ring; or

[0027] 3- or 4-piperidinyl, 3-pyrrolidinyl, 3- or 4- tetrahydropyranyl,3-tetrahydrofuranyl, 3- or 4- tetrahydropyranyl, 3-tetrahydrofuranyl, 3-or 4-tetrahydrothiopyranyl, 3- or 4-(1,1l-dioxo) tetrahydrothiopyranyl,1-azabicyclo[4.4.0]decyl, 8-azabicyclo[3.2.1]octanyl, norbomyl,quinuclidinyl, indolin-2-one-3-yl, 2-(methoximino)-perhydroazepin-6-yl,each optionally substituted with 1 to 5 substituents independentlyselected at each occurrence from R⁷, C₁-C₆ alkyl-OR⁷, C₁-C₆ alkyl-NR⁸R⁹,CONR⁸R⁹, CN, COOR⁷ SO₂NR⁸R⁹, SO₂R⁷;

[0028] R⁶ is selected from H, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, (C₃-C₁₀cycloalkyl) C₁-C₆ alkyl, C₂-C₄ alkenyl, C₁-C₆ arylalkyl, C₁-C₆heteroarylalkyl where aryl or heteroaryl are optionally substituted with1 to 5 substituents independently selected at each occurrence fromhalogen, C₁-C₆ haloalkyl, OR¹³, NR⁸R⁹, C₁-C₆ alkyl-OR¹³, C₁-C₆alkyl-NR⁸R⁹, CONR⁸R⁹, COOR⁷, CN, SO₂NR⁸R⁹, SO₂R⁷, or R⁶ and R², asmentioned above, jointly form, with the 2 nitrogen atoms to which theyare bound, a C₂-C₅ aminoheterocycle optionally substituted at eachoccurrence with R⁷;

[0029] R⁷ is H, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl,(C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, C₁-C₃ haloalkyl,

[0030] or heterocycloalkyl, C₁-C₈ alkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, C₁-C₈ alkanoyl, aroyl, heteroaroyl, aryl,heteroaryl, C₁-C₆ arylalkyl or C₁-C₆ heteroarylalkyl each optionallysubstituted with 1 to 5 substituents independently selected at eachoccurrence from halogen, C₁-C₆ haloalkyl, OR¹³, NR⁸R⁹, C₁-C₆ alkyl-OR¹³,C₁-C₆ alkyl-NR⁸R⁹, CONR⁸R⁹, COOR¹³, CN, SO₂NR⁸R⁹, SO₂R¹³, with theproviso that for SO₂R¹³, R¹³ cannot be H;

[0031] R⁸ and R⁹ are independently selected at each occurrence from H,C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₃-C₁₀ cycloalkenyl,C₂-C₆ alkynyl, heterocycloalkyl, C₁-C₈ alkanoyl, aroyl, heteroaroyl,aryl, heteroaryl, C₁-C₆ arylalkyl or C₁-C₆ heteroarylalkyl, or R⁸ andR⁹, taken together, can form a C₃-C₆ aminocarbocycle or a C₂-C₅aminoheterocycle each optionally substituted at each occurrence withC₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl, (C₃-C₁₀ cycloalkyl)C₁-C₆ alkyl, C₁-C₃ haloalkyl, or heterocycloalkyl, C₁-C₈ alkylsulfonyl,arylsulfonyl, heteroarylsulfonyl, C₁-C₈ alkanoyl, aroyl, heteroaroyl,aryl, heteroaryl, C₁-C₆ arylalkyl or C₁-C₆ heteroarylalkyl;

[0032] R¹¹ is selected from H, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, (C₃-C₁₀cycloalkyl) C₁-C₆ alkyl;

[0033] R¹² is selected from H, aryl, heteroaryl, C₁-C₆ alkyl, C₃-C₁₀cycloalkyl, (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, optionally substituted withOR⁷, NR⁸R⁹, C₃-C₆ aminocarbocycle, or C₂-C₅ aminoheterocycle;

[0034] R¹³ is independently selected at each occurrence from H, C₁-C₆alkyl, C₃-C₁₀ cycloalkyl, (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, with the proviso that when R⁷is SO₂R¹³, R¹³ cannot be H;

[0035] R¹⁴ is H, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, (C₃-C₁₀ cycloalkyl)C₁-C₆ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, halo, or CN;

[0036] or a pharmaceutically acceptable salt, hydrate, or prodrugthereof.

[0037] Preferred compounds of the present invention are those of formulaI where X is N or CH, R¹ is H, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, or(C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl; R⁶ is H, C₁-C₆ alkyl, C₃-C₁₀cycloalkyl, or (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl.

[0038] This invention also encompasses, in additional embodiments, thenovel compounds of formula I, and the salts and solvates thereof, aswell as pharmaceutical formulations comprising a compound of formula I,or a pharmaceutically acceptable salt or solvate thereof, in combinationwith one or more pharmaceutically acceptable carriers, excipients, ordiluents therefor.

[0039] This invention also encompasses methods to treat physiologicaldisorders associated with an excess of neuropeptide Y, such as eatingand cardiovascular disorders, which method comprises administering to amammal in need of said treatment an effective amount of a compound ofthe formula I.

[0040] This invention also encompasses methods of selectively inhibitingbinding of NPY₁ receptor s, which comprises contacting a compound offormula I with neuronal cells, wherein the compound is present in anamount effective to produce a concentration sufficient to inhibitbinding of NPY₁ receptors in vitro.

DETAILED DESCRIPTION OF THE INVENTION

[0041] The current invention concerns the discovery that a select groupof aminoalkyl substituted 4-amino pyrazolopyrimidines and 7-aminopyrazolo triazines, those of formula I, which are novel and usefulneuropeptide Y receptor antagonists.

[0042] In certain situations, the compounds of formula I may contain oneor more asymmetric carbon atoms, so that the compounds can exist indifferent stereoisomeric forms. These compounds can be, for example,racemates or optically active forms. In these situations, the singleenantiomers, i.e., optically active forms, can be obtained by asymmetricsynthesis or by resolution of the racemates. Resolution of the racematescan be accomplished, for example, by conventional methods such ascrystallization in the presence of a resolving agent, or chromatography,using, for example a chiral HPLC column.

[0043] Representative compounds of the present invention, which areencompassed by formula I, include, but are not limited to the compoundsin Examples 1-306 and their pharmaceutically acceptable acid additionsalts. In addition, if the compound of the invention is obtained as anacid addition salt, the free base can be obtained by basifying asolution of the acid salt. Conversely, if the product is a free base, anaddition salt, particularly a pharmaceutically acceptable addition salt,may be produced by dissolving the free base in a suitable organicsolvent and treating the solution with an acid, in accordance withconventional procedures for preparing acid addition salts from basecompounds.

[0044] Non-toxic pharmaceutical salts include salts of acids such ashydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic,toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric,maleic, hydroiodic, alkanoic such as acetic, HOOC—(CH₂)_(n)—COOH where nis 0-4, and the like. Those skilled in the art will recognize a widevariety of non-toxic pharmaceutically acceptable addition salts.

[0045] The present invention also encompasses the acylated prodrugs ofthe compounds of formula I. “Prodrugs” are considered to be anycovalently bonded carriers which release the active parent drug offormula I in vivo when such prodrug is administered to a mammaliansubject. Prodrugs of the compounds of the invention are prepared bymodifying functional groups present in the compounds in such a way thatthe modifications are cleaved, either in routine manipulation or in vivoto the parent compounds. Prodrugs include compounds wherein hydroxy,amine, or sulfhydryl groups are bonded to any group that, whenadministered to a mammalian subject, cleaves to form a free hydroxyl,amino, or sulfhydryl group, respectively. Examples of prodrugs include,but are not limited to, acetate, formate, and benzoate derivatives ofalcohol and amine functional groups in the compounds of formula I; andthe like. Those skilled in the art will recognize various syntheticmethodologies which may be employed to prepare non-toxicpharmaceutically acceptable addition salts and acylated prodrugs of thecompounds encompassed by formula I.

[0046] Where a compound exists in various tautomeric forms, theinvention is not limited to any one of the specific tautomers. Theinvention includes all tautomeric forms of a compound.

[0047] By “heteroatom” in the present invention is meant oxygen orsulfur, or a nitrogen atom optionally substituted by C₁-C₆ lower alkyl,C₁-C₆ arylalkyl, C₁-C₁₀ cycloalkyl, (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl,C₂-C₈ alkanoyl, C₁-C₆ sulfonyl.

[0048] By “alkyl”, “lower alkyl”, or “C₁-C₆ alkyl” in the presentinvention is meant straight or branched chain alkyl groups having 1-6carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl,n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl,hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.

[0049] By “cycloalkyl”, or “C₃-C₁₀ cycloalkyl” in the present inventionis meant alkyl groups having 3-10 carbon atoms forming a mono-, bi-, orpolycyclic ring system, such as, for example, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, norbomyl, and the like.

[0050] By “(cycloalkyl)alkyl”, “lower (cycloalkyl)alkyl”, or (C₃-C₁₀cycloalkyl) C₁-C₆ alkyl in the present invention is meant a straight orbranched alkyl substituent formed of 1 to 6 carbon atoms attached to amono-, bi, or polycyclic ring system having 3-10 carbon atoms, such as,for example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, cycloheptylmethyl, and the like.

[0051] The term “C₂-C₆ alkenyl” in the present invention meanshydrocarbon chains having 2 to 6 carbons in a straight or branchedarrangement and containing one or more unsaturated carbon-carbon doublebonds which may occur in any stable point along the chain, such as, forexample, ethenyl, allyl, isopropenyl, and the like.

[0052] By “cycloalkenyl” or “C₃-C₁₀ cycloalkenyl” in the presentinvention is meant alkyl groups having 3-10 carbon atoms forming amono-, bi, or polycyclic ring system having 3-10 carbon atoms andcontaining one or more carbon-carbon double bonds which may occur in anystable point in the ring, such as, for example, cyclopentenyl,cyclohexenyl, or cycloheptenyl.

[0053] The term “C₂-C₆ alkynyl” in the present invention meanshydrocarbon chains having 2 to 6 carbons in a straight or branchedarrangement and containing one or more unsaturated carbon-carbon triplebonds which may occur in any stable point along the chain, such as, forexample, ethynyl, propargyl, and the like.

[0054] The term “aryl” in the present invention means a monocyclic orbicyclic aromatic group having preferably 6 to 10 carbon atoms, such as,for example, phenyl or naphthyl.

[0055] The term “heteroaryl” in the present invention means an arylgroup in which one or more of the ring(s) carbon atoms have beenreplaced with a heteroatom. Such groups preferably have 4 to 10 carbonatoms and 1 to 4 heteroatoms, such as, for example, pyridyl,pyrimidinyl, triazinyl, imidazolyl, oxazolyl, isoxazolyl, indolyl,pyrrolyl, pyrazolyl, quinolinyl, isoquinolinyl, thiazolyl,benzothiadiazolyl, triazolyl, triazinyl, pyrazinyl, furanyl, thienyl,benzothienyl, benzofuranyl, tetrazolyl.

[0056] The term “heterocyclyl”, “heterocycle” or “heterocycloalkyl” inthe present invention means a saturated or partially saturatedheteroaryl group.

[0057] By “C₁-C₆ arylalkyl” or “C₁-C₆ heteroarylalkyl” in the presentinvention is meant a branched or straight-chain alkyl group having 1-6carbon atoms and substituted on one of the carbon atoms by an optionallysubstituted aryl or heteroaryl ring, such as, for example, benzyl,phenethyl, methylpyridyl, ethylpyridyl, and the like.

[0058] By “C₅-C₈ arylcycloalkyl” in the present invention is meantcycloalkyl groups having 5-8 carbon atoms and fused to an aryl group,such as, for example, 1,2,3,4 tetrahydronaphthalenyl,2,3-dihydrobenzothienyl, or 2,3-dihydobenzofuranyl.

[0059] By “C₅-C₈ heteroarylcycloalkyl” in the present invention is meantcycloalkyl groups having 5-8 carbon atoms fused to a heteroaryl group,such as, for example, 1,2,3,4 tetrahydroquinolyl,2,3-dihydrobenzothienyl, 2,3-dihydobenzofuranyl, or indolinyl.

[0060] By “alkoxy”, “C₁-C₆ alkoxy”, or “C₁-C₆ alkyloxy” in the presentinvention is meant straight or branched chain alkoxy groups having 1-6carbon atoms, such as, for example, methoxy, ethoxy, propoxy,isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyl,isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.

[0061] By “cycloalkoxy”, “C₃-C₁₀ cycloalkoxy”, or “C₃-C₁₀ cycloalkyloxy”in the present invention is meant a group formed by an oxygen atomattached to a mono-, bi, or polycyclic ring system having 3-10 carbonatoms, such as, for example, cyclopropoxy, cyclobutoxy, cyclopentoxy,cyclohexoxy, or cycloheptoxy.

[0062] By “(cycloalkyl)alkyloxy”, “(C₃-C₁₀ cycloalkyl) C₁-C₆ alkoxy”, or“(C₃-C₁₀ cycloalkyl) C₁-C₆ alkyloxy” in the present invention is meant agroup formed by an oxygen atom attached to a 1-6 carbon chain linked toa mono-, bi, or polycyclic ring system having 3-10 carbon atoms, suchas, for example, cyclopropylmethyloxy, cyclobutylmethyloxy,cyclopentylmethyloxy, cyclohexylmethyloxy, cycloheptylmethyloxy, and thelike.

[0063] By “C₃-C₆ aminocarbocycle” is meant a cyclic amino group formedby a nitrogen contained in a ring having 3 to 6 carbon atoms, such as,for example, azetidino, pyrrolidino, piperidino, perhydroazepino.

[0064] By “C₂-C₅ aminoheterocycle” is meant a cyclic amino group formedby a nitrogen contained in a ring having 2 to 5 carbon atoms and oneother heteroatom, such as, for example, morpholino, thiomorpholino,piperazino.

[0065] By the terms “halo” or “halogen” in the present invention ismeant fluoro, chloro, bromo, and iodo.

[0066] “Haloalkyl” is intended to include both branched andstraight-chain alkyl having the specified number of carbon atomssubstituted with 1 or more halogens.

[0067] The term “C₂-C₈ alkanoyl” means an acyl group with 2 to 8 carbonatoms in a linear, branched, or C₃-C₁₀ cycloalkyl arrangement,optionally substituted with 1 to 5 substituents independently selectedat each occurrence from halogen, trifluoromethyl, OR⁷, NR⁸R⁹, CONR⁸R⁹,COOR⁷, or CN.

[0068] The term “C₁-C₆ alkyl sulfonyl” means an alkylsulfonyl groupcontaining 1 to 6 carbon atoms in a linear, branched, or C₃-C₇cycloalkyl arrangement.

[0069] The term “substituted” means that one or more hydrogen on thedesignated atom is replaced by the specified group, provided that thevalence on the designated atom is not exceeded, and that a chemicallystable compound results from the substitution.

[0070] A stable compound is defined herein as one that can be isolated,characterized, and tested for biological activity.

[0071] The term “oxo” (i.e. ═O) indicates that two geminal hydrogenatoms are replaced by a double-bond oxygen group.

[0072] The term “hydroximino” (i.e. ═N—OH) ) indicates that two geminalhydrogen atoms are replaced by a double-bond nitrogen atom substitutedwith a hydroxyl group.

[0073] The term “C₁-C₆ alkoximino” (i.e. ═N—O-Alkyl) indicates that twogeminal hydrogen atoms are replaced by a double-bond nitrogen atomsubstituted with a C₁-C₂ alkoxy group, such as, for example, methoximino(═N—OMe).

[0074] In the present invention, some of the groups specificallymentioned above are defined as follows:

[0075] Unless specified, the point of attachment may occur in any stablepoint along the above-mentioned rings.

[0076] In the present invention, the term “potent” in the context ofNPY₁ receptor antagonists qualifies a binding affinity with a Ki of lessthan 10 micromolar, preferably less than 1 micromolar, and morepreferably less than 100 nanomolar in the human NPY, binding assay.

[0077] In the present invention, the term “selective” in the context ofNPY₁ receptor antagonists qualifies a binding affinity with a Ki in thehuman NPY₁ binding assay that is 10-fold, preferably 100-fold, and morepreferably 1000-fold, less than the Ki of the same compound measured inanother receptor binding assay, in particular the NPY₅ and the CRF₁receptor binding assays. Binding assays for the NPY₅ and CRF₁ receptorshave been described, for example, in J. Clin. Invest., 102 2136 (1998)and in Endocrinology 116, 1653 (1985), respectively.

[0078] As the compounds of formula I are selective antagonists of the Y₁receptor, they are of value in the treatment of a wide variety ofclinical conditions which are characterized by the presence of an excessof neuropeptide Y. Thus, the invention provides methods for thetreatment or prevention of a physiological disorder associated with anexcess of neuropeptide Y, which method comprises administering to amammal in need of said treatment an effective amount of a compound offormula I or a pharmaceutically acceptable salt, solvate or prodrugthereof. The term “physiological disorder associated with an excess ofneuropeptide Y” encompasses those disorders associated with aninappropriate stimulation of neuropeptide Y receptors, regardless of theactual amount of neuropeptide Y present locally. These physiologicaldisorders may include: disorders or diseases pertaining to the heart,blood vessels or the renal system, such as vasospasm, heart failure,shock, cardiac hypertrophy increased blood pressure, angina, myocardialinfarction, sudden cardiac death, arrhythmia, peripheral vasculardisease, and abnormal renal conditions such as impaired flow of fluid,abnormal mass transport, or renal failure; conditions related toincreased sympathetic nerve activity for example, during or aftercoronary artery surgery, and operations and surgery in thegastrointestinal tract; cerebral diseases and diseases related to thecentral nervous system, such as cerebral infarction, neurodegeneration,epilepsy, stroke, and conditions related to stroke, cerebral vasospasmand hemorrhage, depression, anxiety, schizophrenia, and dementia;conditions related to pain or nociception; diseases related to abnormalgastrointestinal motility and secretion, such as different forms ofileus, urinary incontinence, and Crohn's disease; abnormal drink andfood intake disorders, such as obesity, anorexia, bulimia, and metabolicdisorders; diseases related to sexual dysfunction and reproductivedisorders; conditions or disorders associated with inflammation;respiratory diseases, such as asthma and conditions related to asthmaand bronchoconstriction; and diseases related to abnormal hormonerelease, such as leutinizing hormone, growth hormone, insulin, andprolactin.

[0079] The compounds of general formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques. In addition, there isprovided a pharmaceutical formulation comprising a compound of generalformula I and a pharmaceutically acceptable carrier. One or morecompounds of general formula I may be present in association with one ormore non-toxic pharmaceutically acceptable carriers and/or diluentsand/or adjuvants and if desired other active ingredients. Thepharmaceutical compositions containing compounds of general formula Imay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.

[0080] Compositions intended for oral use may be prepared according toany method known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed.

[0081] Formulations for oral use may also be presented as hard gelatincapsules wherein the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules wherein the active ingredient is mixed withwater or an oil medium, for example peanut oil, liquid paraffin or oliveoil. Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

[0082] Oily suspensions may be formulated by suspending the activeingredients in a vegetable oil, for example arachid oil, olive oil,sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.The oily suspensions may contain a thickening agent, for examplebeeswax, hard paraffin or cetyl alcohol. Sweetening agents such as thoseset forth above, and flavoring agents may be added to provide palatableoral preparations. These compositions may be preserved by the additionof an anti-oxidant such as ascorbic acid.

[0083] Dispersible powders and granules suitable for preparation of anaqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives. Suitable dispersing or wettingagents and suspending agents are exemplified by those already mentionedabove. Additional excipients, for example sweetening, flavoring andcoloring agents, may also be present.

[0084] Pharmaceutical compositions of the invention may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oil,for example olive oil or arachid oil, or a mineral oil, for exampleliquid paraffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. , The emulsions may also containsweetening and flavoring agents.

[0085] Syrups and elixirs may be formulated with sweetening agents, forexample glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, a preservative and flavoringand coloring agents. The pharmaceutical compositions may be in the formof a sterile injectable aqueous or oleaginous suspension. Thissuspension may be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents which havebeen mentioned above. The sterile injectable preparation may also besterile injectable solution or suspension in a non-toxic parenterallyacceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono-or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

[0086] The compounds of general formula I may also be administered inthe form of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

[0087] Compounds of general formula I may be administered parenterallyin a sterile medium. The drug, depending on the vehicle andconcentration used, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

[0088] Dosage levels of the order of from about 0.1 mg to about 50 mgper kilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 3 g per patient perday), although higher amounts for example up to 140 mg/kg/day may beappropriate in some circumstances. The amount of active ingredient thatmay be combined with the carrier materials to produce a single dosageform will vary depending upon the host treated and the particular modeof administration. Dosage unit forms will generally contain between fromabout 1 mg to about 500 mg of an active ingredient.

[0089] It will be understood, however, that the specific dose level forany particular patient will depend upon a variety of factors includingthe activity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

[0090] In appropriate cases, the compounds of the invention may beemployed in combination with other active agents. The inventiontherefore also provides pharmaceutical combination compositionscomprising a therapeutically effective amount of a compositioncomprising: (a) first compound, said first compound being a compound ofthe type descibed above a prodrug thereof, or a pharmaceuticallyacceptable salt of said compound or of said prodrug; and (b) a secondcompound, said second compound being a gonist, a thyromimetic, an eatingbehavior modifying agent or a NPY antagonist; and a pharmaceuticalcarrier, vehicle, diluent. Combinations may, for example comprise (a)first compound, said first compound being a compound as described abovea prodrug thereof, or a pharmaceutically acceptable salt of saidcompound or of said prodrug; (b) a second compound, said second compoundbeing an aldose reductase inhibitor, a glycogen phosphorylase inhibitor,a sorbitol dehydrogenase inhibitor, insulin metformin, acarbose, athiazolidinedione, a glitazone, rezulin, trogitalazone, a sulfonylurea,glipazide, glyburide, or chlorpropamide; (c) a pharmaceutical carrier,vehicle, or diluent. In other cases, a kit may be appropriatecomprising: (a) first compound, said first compound being a compound ofclaim 24 or 25, a prodrug thereof, or a pharmaceutically acceptable saltof said compound or of said prodrug; (b) a second compound, said secondcompound being a P3 agonist, a thyromimetic, an eating behaviormodifying agent or a NPY antagonist; and a pharmaceutical carrier,vehicle, diluent; and (c) means for containing said first and secondunit dosage forms wherein the amounts of the first and second compoundsresult in a therapeutic effect.

[0091] Preparation of Aminoalkyl SubstitutedPyrazolo[1,5,-al-1,5-Pyrimidines and Pyrazolor[1,5-a]-1,3,5-TriazinesDerivatives

[0092] One general approach is to convert a heterocyclic core A and or aheterocyclic core B

[0093] to a compound that exhibits a K_(i) of 5 micromolar or less in anassay of NPY receptor binding, wherein the substituents are as definedabove by substituting the 7-position of the heterocyclic core A or the4-position of the heterocyclic core B with a diamine group—N[R²]—A—B—N[R⁶]—R⁵.

[0094] An illustration of preparation methods of compounds of thepresent invention is given in the Schemes below. In particulardisplacement of a leaving group Z, as in formula 10 (Scheme 1) by theappropriate substituted amine provides a method to convert theheterocyclic cores of the present invention, i.e. aryl or heteroarylsubstituted pyrazolo[1,5,-a]-1,5-pyrimidines andpyrazolo[1,5-a]-1,3,5-triazines, into compounds that potently interactwith the NPY1 receptor. Such transformations may require severalconsecutive chemical steps. Those having skill in the art will recognizethat the starting materials may be varied and additional steps employedto produce compounds encompassed by the present invention. Thedisclosures of all articles and references mentioned in thisapplication, including patents, are incorporated herein by reference.

[0095] As illustrated in Scheme 1, compounds of formula I can beprepared from intermediate compounds of formula 10, where Z is halogen(preferably chloro or bromo), alkane sulfonyloxy, aryl sulfonyloxy orhaloalkane sulfonyloxy, and X, R¹, R³ and R⁴ are defined above, usingthe procedures outlined below.

[0096] Compounds of formula 10 react with an amine of formulaH₂N—A—B—N[R⁶]—R⁵, where A,B, R⁵ and R⁶ are defined as above, in thepresence or absence of a base in the presence or absence of an inertsolvent at reaction temperatures ranging from −78° C. to 250° C. togenerate compounds of formula I. Bases may include, but are not limitedto, alkali metal hydrides (preferably sodium hydride), alkali metalalkoxides (1-6 carbons) (preferably sodium methoxide, sodium ethoxide,or sodium tert-butoxide), alkaline earth metal hydrides, alkali metaldialkylamides (preferably lithium diisopropylamide), alkali metalcarbonates, alkali metal bicarbonates, alkali metalbis-(trialkylsilyl)amides (preferably lithium or sodium(trimethylsilyl)amide), trialkylamines (preferablyN,N-di-isopropyl-N-ethyl amine or triethylamine), arylamines (preferably4-dimethyl aniline), or heteroaromatic amines (preferably pyridine).Inert solvents may include, but are not limited to, alkyl alcohols (1-8carbons) (preferably methanol, ethanol, or tert-butanol), loweralkanenitriles (1-6 carbons) (preferably acetonitrile), dialkyl ethers(preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or1,4-dioxane), N,N-dialkylformamides (preferably dimethyl formamide),N,N-dialkylacetamides (preferably dimethyl acetamide), cyclic amides(preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferablydimethylsulfoxide), aromatic hydrocarbons (preferably benzene ortoluene), or haloalkanes (1-10 carbons and 1-10 halogens) (preferablydichloromethane). Preferred reaction temperatures range from 0° C. to 140° C.

[0097] Alternatively, as shown in Scheme 2, compounds of formula I canbe obtained by first reacting a compound of formula 10 with an aminoalcohol of formula H₂N—A—B—OH, where A and B are defined as above, inthe presence or absence of a base in the presence or absence of an inertsolvent at reaction temperatures ranging from −78° C. to 250° C. togenerate intermediates of formula 11. Reacting a compound of formula 11with a halogenating agent or sulfonylating agent in the presence orabsence of a base in the presence or absence of an inert solvent atreaction temperatures ranging from −78° C. to 250° C. to afford productsof formula 12a (where Z is halogen, alkane sulfonyloxy, aryl sulfonyloxyor haloalkane sulfonyloxy) or 12b when A and B are both CH₂ and X isCR¹⁴. Halogenating agents include, but are not limited to, SOCl₂, POCl₃,PCl₃, PCl₅, POBr₃, PBr₃, PBr₅., CCl₄/PPh₃. Sulfonylating agents include,but are not limited to, alkanesulfonyl halides or anhydrides (preferablymethanesulfonyl chloride or methanesulfonic anhydride), aryl sulfonylhalides or anhydrides (such as p-toluenesulfonyl chloride or anhydride),or haloalkylsulfonyl halides or anhydrides (preferablytrifluoromethanesulfonic anhydride). Bases may include, but are notlimited to, trialkylamines (preferably N,N-di-isopropyl-N-ethyl amine ortriethylamine), bicyclic amidines (preferably DBU), anilines (preferablyN-dimethyl aniline), or heteroaromatic amines (preferably pyridine).Inert solvents may include, but are not limited to, lower alkanenitriles(1-6 carbons) (preferably acetonitrile), dialkyl ethers (preferablydiethyl ether), cyclic ethers (preferably tetrahydrofuran or1,4-dioxane), N,N-dialkylformamides (preferably dimethyl formamide),N,N-dialkylacetamides (preferably dimethyl acetamide), cyclic amides(preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferablydimethylsulfoxide), aromatic hydrocarbons (preferably benzene ortoluene), or haloalkanes with 1-10 carbons and 1-10 halogens (preferablydichloromethane). Preferred reaction temperatures range from −20° C. to100° C. Compounds of formula 12a or 12b can then be reacted with anamine of formula HN[R⁶]—R⁵, where R⁵ and R⁶ are defined as above, togive a compound of formula I. Bases may include, but are not limited to,alkali metal hydrides (preferably sodium hydride), alkali metalalkoxides (1-6 carbons) (preferably sodium methoxide, sodium ethoxide,or sodium tert-butoxide), alkaline earth metal hydrides, alkali metaldialkylamides (preferably lithium diisopropylamide), alkali metalcarbonates, alkali metal bicarbonates, alkali metalbis-(trialkylsilyl)amides (preferably lithium or sodium(trimethylsilyl)amide), trialkylamines (preferablyN,N-di-isopropyl-N-ethyl amine or triethylamine), arylamines (preferably4-dimethyl aniline), or heteroaromatic amines (preferably pyridine).Inert solvents may include, but are not limited to, alkyl alcohols (1-8carbons) (preferably methanol, ethanol, or tert-butanol), loweralkanenitriles (1-6 carbons) (preferably acetonitrile), dialkyl ethers(preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or1,4-dioxane), N,N-dialkylfornamides (preferably dimethyl formamide),N,N-dialkylacetamides (preferably dimethyl acetamide), cyclic amides(preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferablydimethylsulfoxide), aromatic hydrocarbons (preferably benzene ortoluene), or haloalkanes (1-10 carbons and 1-10 halogens) (preferablydichloromethane). Preferred reaction temperatures range from 0° C. to140° C.

[0098] A subset of compounds of formula I, described under formula Ia inScheme 3, can be obtained by first reacting a compound of formula 10with a diamine of formula H₂N—A—B—NH₂, where A and B are defined asabove, in the presence or absence of a base in the presence or absenceof an inert solvent at reaction temperatures ranging from −78° C. to250° C. to generate intermediates of formula 13. Reaction of a compoundof formula 13 with a ketone of Formula Re—C═O—Re or an aldehyde ofFormula R^(a)—C═O—R^(b) where R^(b)═H, in the presence of a reducingagent provides a compound of formula Ia, where the groupingR^(a)—CH—R^(b) corresponds to R⁵ in formula I, as defined above.Reducing agents include, but are not limited to, alkali metal oralkaline earth metal borohydrides (preferably lithium or sodiumborohydride), borane (preferably complexed with dimethyl sulfide ortetrahydrofuran), dialkylboranes (such as di-isoamylborane), alkalimetal aluminum hydrides (preferably lithium aluminum hydride), alkalimetal (trialkoxy)aluminum hydrides (such as triethoxyaluminum hydride),dialkyl aluminum hydrides (such as di-isobutyl aluminum hydride), alane(preferably complexed with dimethylethylamine). Inert solvents mayinclude, but are not limited to, alkyl alcohols (1-6 carbons)(preferably methanol, ethanol, or tert-butanol), dialkyl ethers(preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or1,4-dioxane), aromatic hydrocarbons (preferably benzene or toluene).Preferred reaction temperatures range from −78° C. to 100° C.

[0099] Alternatively, as illustrated in Scheme 4, a subset of compoundsof formula I, described under formula Ib, can be obtained by firstreacting a compound of formula 13 with an activated acid of formulaR^(c)—C═O—Z, where Z is halo (preferably chloro), O-acyl (preferablyO—C═O—R^(c)), in the presence or absence of a base in the presence orabsence of an inert solvent at reaction temperatures ranging from −78°C. to 250° C. to generate an amide intermediate of formula 14. Reactionof a compound of formula 14 with a reducing agent provides a compound offormula lb, where the grouping R^(c)—CH₂ corresponds to R⁵ in formula I,as defined above. Reducing agents include, but are not limited to,alkali metal or alkaline earth metal borohydrides (preferably lithium orsodium borohydride), borane (preferably complexed with dimethyl sulfideor tetrahydrofuran), dialkylboranes (such as di-isoamylborane), alkalimetal aluminum hydrides (preferably lithium aluminum hydride), alkalimetal (trialkoxy)aluminum hydrides (such as triethoxyaluminum hydride),dialkyl aluminum hydrides (such as di-isobutyl aluminum hydride), alane(preferably complexed with dimethylethylamine). Inert solvents mayinclude, but are not limited to, alkyl alcohols (1-6 carbons)(preferably methanol, ethanol, or tert-butanol), dialkyl ethers(preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or1,4-dioxane), aromatic hydrocarbons (preferably benzene or toluene).Preferred reaction temperatures range from −78° C. to 100° C.

[0100] Alternatively, a subset of compounds of formula I, describedunder formula Ic in Scheme 5, can be obtained by first reacting acompound of formula 10 with an amine of formulaH₂N—A—CH(OR^(c))(OR^(d)), where A is defined above, and R^(c) and R^(d)are C₁-C₆ lower alkyls or, taken together, complete a ketal group, suchas, for example a dioxane or dioxolane group, in the presence or absenceof a base in the presence or absence of an inert solvent at reactiontemperatures ranging from −78° C. to 250° C. to generate compounds offormula 15. Bases may include, but are not limited to, alkali metalhydrides (preferably sodium hydride), alkali metal alkoxides (1-6carbons) (preferably sodium methoxide, sodium ethoxide, or sodiumtert-butoxide), alkaline earth metal hydrides, alkali metaldialkylamides (preferably lithium diisopropylamide), alkali metalcarbonates, alkali metal bicarbonates, alkali metalbis-(trialkylsilyl)amides (preferably lithium or sodium(trimethylsilyl)amide), trialkylamines (preferablyN,N-di-isopropyl-N-ethyl amine or triethylamine), arylamines (preferably4-dimethyl aniline), or heteroaromatic amines (preferably pyridine).Inert solvents may include, but are not limited to, alkyl alcohols (1-8carbons) (preferably methanol, ethanol, or tert-butanol), loweralkanenitriles (1-6 carbons) (preferably acetonitrile), dialkyl ethers(preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or1,4-dioxane), N,N-dialkylformamides (preferably dimethyl formamide),N,N-dialkylacetamides (preferably dimethyl acetamide), cyclic amides(preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferablydimethylsulfoxide), aromatic hydrocarbons (preferably benzene ortoluene), or haloalkanes (1-10 carbons and 1-10 halogens) (preferablydichloromethane). Compounds of formula 15 react with a protic acid inthe presence or absence of an inert solvent at reaction temperaturesranging from −78° C. to 250° C., followed by aqueous work-up to generatecompounds of formula 16. Inert solvents may include, but are not limitedto dialkyl ethers (preferably diethyl ether), cyclic ethers (preferablytetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferablydimethyl formamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one),dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons(preferably benzene or toluene), or haloalkanes (1-10 carbons and 1-10halogens) (preferably dichloromethane). Protic acids include, but arenot limited to, formic acid, acetic acid, trifluoroacetic acid,hydrochloric acid, methane sulfonic acid. Alternatively, compounds offormula 16 can be obtained by oxidation of compounds of formula 11 whereB═CH₂. Oxidizing agents include, but are not limited to, transitionmetal oxides, such as CrO₃ or MnO₂, pyridine-chromium complexes, such asCrO₃.C₅H₅N, pyridinium dichromate or pyridinium chlorochromate, or anoxalyl chloride-DMSO-triethylamine reagent (Swern oxidation). Compoundsof formula 16 react with amines of formula H₂N—R⁵, where R⁵ is definedabove, in the presence of a reducing agent in the presence or absence ofan inert solvent in the presence or absence of a protic acid attemperatures ranging from −78° C. to 100° C., to give compounds offormula Ic. Reducing agents include, but are not limited to, alkalimetal or alkaline earth metal borohydrides (preferably lithium or sodiumborohydride), borane (preferably complexed with dimethyl sulfide ortetrahydrofuran), dialkylboranes (such as di-isoamylborane), alkalimetal aluminum hydrides (preferably lithium aluminum hydride), alkalimetal (trialkoxy)aluminum hydrides (such as triethoxyaluminum hydride),dialkyl aluminum hydrides (such as di-isobutyl aluminum hydride), alane(preferably complexed with dimethylethylamine). Inert solvents mayinclude, but are not limited to, alkyl alcohols (1-6 carbons)(preferably methanol, ethanol, or tert-butanol), dialkyl ethers(preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or1,4-dioxane), aromatic hydrocarbons (preferably benzene or toluene).

[0101] When X is CR¹⁴, as defined above, compounds of formula 10 may beobtained from compounds of formula 22, as shown in Scheme 6. Compoundsof formula 22 can be reacted with compounds of formulaR—C═O—CH(R¹⁴)C═O—R^(c), where R¹ and R¹⁴ are defined above, and R^(c) ishalogen, cyano, lower alkoxy (1-6 carbons), or lower alkanoyloxy (1-6carbons), in the presence or absence of a base in an inert solvent atreaction temperatures ranging from −50° C. to 250° C. to affordcompounds of formula 23a. Bases may include, but are not limited to,alkali metal hydrides (preferably sodium hydride), alkali metalalkoxides (1-6 carbons) (preferably sodium methoxide, sodium ethoxide,or sodium tert-butoxide), alkaline earth metal hydrides, alkali metaldialkylamides (preferably lithium diisopropylamide), alkali metalcarbonates, alkali metal hydroxides, alkali metalbis-(trialkylsilyl)amides (preferably lithium or sodium(trimethylsilyl)amide), trialkylamines (preferablyN,N-di-isopropyl-N-ethyl amine or triethylamine), bicyclic amidines(preferably DBU), or heteroaromatic amines (preferably pyridine). Inertsolvents may include, but are not limited to, alkyl alcohols (1-8carbons) (preferably methanol, ethanol, or tert-butanol), loweralkanenitriles (1-6 carbons) (preferably acetonitrile), water, dialkylethers (preferably diethyl ether), cyclic ethers (preferablytetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferablydimethyl formamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one),dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons(preferably benzene or toluene). Compounds of formula 23a can then bereacted with a halogenating agent or sulfonylating agent in the presenceor absence of a base in the presence or absence of an inert solvent atreaction temperatures ranging from −78° C. to 250° C. to afford productsof formula 10 (where Z is halogen, alkane sulfonyloxy, aryl sulfonyloxyor haloalkane sulfonyloxy and X is CR¹⁴). Halogenating agents include,but are not limited to, SOCl₂, POCl₃, PCl₃, PCl₅, POBr₃, PBr₃, or PBr₅.Sulfonylating agents include, but are not limited to, alkanesulfonylhalides or anhydrides (preferably methanesulfonyl chloride ormethanesulfonic anhydride), aryl sulfonyl halides or anhydrides (such asp-toluenesulfonyl chloride or anhydride), or haloalkylsulfonyl halidesor anhydrides (preferably trifluoromethanesulfonic anhydride). Bases mayinclude, but are not limited to, trialkylamines (preferablyN,N-di-isopropyl-N-ethyl amine or triethylamine), bicyclic amidines(preferably DBU), anilines (preferably N-dimethyl aniline), orheteroaromatic amines (preferably pyridine). Inert solvents may include,but are not limited to, lower alkanenitriles (1-6 carbons) (preferablyacetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers(preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides(preferably dimethyl formamide), N,N-dialkylacetamides (preferablydimethyl acetamide), cyclic amides (preferablyN-methylpyrrolidin-2-one), dialkylsulfoxides (preferablydimethylsulfoxide), aromatic hydrocarbons (preferably benzene ortoluene), or haloalkanes with 1-10 carbons and 1-10 halogens (preferablydichloromethane). Preferred reaction temperatures range from −20° C. to100° C.

[0102] As shown in Scheme 7, when X is N, compounds of formula 22 can bereacted with compounds of formula R—C═N(COOR^(g))—OR^(f), where R¹ isdefined above, and R^(g) is lower alkyl (1-6 carbons), and R^(f) ishalogen, cyano, lower alkoxy (1-6 carbons), or lower alkanoyloxy (1-6carbons), in the presence or absence of a base in an inert solvent atreaction temperatures ranging from −50° C. to 250° C. to affordcompounds of formula 23b. Bases may include, but are not limited to,alkali metal hydrides (preferably sodium hydride), alkali metalalkoxides (1-6 carbons) (preferably sodium methoxide, sodium ethoxide,or sodium tert-butoxide), alkaline earth metal hydrides, alkali metaldialkylamides (preferably lithium diisopropylamide), alkali metalcarbonates, alkali metal hydroxides, alkali metalbis-(trialkylsilyl)amides (preferably lithium or sodium(trimethylsilyl)amide), trialkylamines (preferablyN,N-di-isopropyl-N-ethyl amine or triethylamine), bicyclic amidines(preferably DBU), or heteroaromatic amines (preferably pyridine). Inertsolvents may include, but are not limited to, alkyl alcohols (1-8carbons) (preferably methanol, ethanol, or tert-butanol), loweralkanenitriles (1-6 carbons) (preferably acetonitrile), water, dialkylethers (preferably diethyl ether), cyclic ethers (preferablytetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferablydimethyl formamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one),dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons(preferably benzene or toluene), heteroaromatic hydrocarbons (preferablypyridine). Compounds of formula 23b can then be reacted with ahalogenating agent or sulfonylating agent in the presence or absence ofa base in the presence or absence of an inert solvent at reactiontemperatures ranging from −78° C. to 250° C. to afford products offormula 10 (where Z is halogen, alkane sulfonyloxy, aryl sulfonyloxy orhaloalkane sulfonyloxy and X is N). Halogenating agents include, but arenot limited to, SOCl₂, POCl₃, PCl₃, PCl₅, POBr₃, PBr₃, or PBr₅.Sulfonylating agents include, but are not limited to, alkanesulfonylhalides or anhydrides (preferably methanesulfonyl chloride ormethanesulfonic anhydride), aryl sulfonyl halides or anhydrides (such asp-toluenesulfonyl chloride or anhydride), or haloalkylsulfonyl halidesor anhydrides (preferably trifluoromethanesulfonic anhydride). Bases mayinclude, but are not limited to, trialkylamines (preferablyN,N-di-isopropyl-N-ethyl amine or triethylamine), bicyclic amidines(preferably DBU), anilines (preferably N-dimethyl aniline), orheteroaromatic amines (preferably pyridine). Inert solvents may include,but are not limited to, lower alkanenitriles (1-6 carbons) (preferablyacetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers(preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides(preferably dimethyl formamide), N,N-dialkylacetamides (preferablydimethyl acetamide), cyclic amides (preferablyN-methylpyrrolidin-2-one), dialkylsulfoxides (preferablydimethylsulfoxide), aromatic hydrocarbons (preferably benzene ortoluene), or haloalkanes with 1-10 carbons and 1-10 halogens (preferablydichloromethane). Preferred reaction temperatures range from −20° C. to100° C.

[0103] Alternatively, as illustrated in Scheme 8, compounds of formula23b can be obtained by first reacting compounds of formula 22 withcompounds of the formula R¹—(C═NH)—OR^(h), where R¹ is defined above andRI is a lower alkyl group (preferably methyl or ethyl), in the presenceor absence of an acid in an inert solvent to give an intermediate offormula 24. Compounds of formula 24 react with a compound of formulaR^(i)—C═O—R¹, where R¹ and R^(j) are each or independently lower alkoxy(preferably methoxy or ethoxy), 1-imidazolyl, halo, aryloxy (preferably4-nitrophenoxy) in the presence or YES absence of an inert solvent toafford compounds of formula 23b. Bases may include, but are not limitedto, alkali metals (preferably sodium), alkali metal hydrides (preferablysodium hydride). alkali metal alkoxides (1-6 carbons) (preferably sodiummethoxide, sodium ethoxide, or sodium tert-butoxide), alkaline earthmetal hydrides, alkali metal dialkylamides (preferably lithiumdiisopropylamide), alkali metal carbonates, alkali metal hydroxides,alkali metal bis-(trialkylsilyl)amides (preferably lithium or sodium(trimethylsilyl)amide), trialkylamines (preferablyN,N-di-isopropyl-N-ethyl amine or triethylamine), bicyclic amidines(preferably DBU), or heteroaromatic amines (preferably pyridine). Inertsolvents may include, but are not limited to, alkyl alcohols (1-8carbons) (preferably methanol, ethanol, or tert-butanol), loweralkanenitriles (1-6 carbons) (preferably acetonitrile), water, dialkylethers (preferably diethyl ether), cyclic ethers (preferablytetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferablydimethyl formamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one),dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons(preferably benzene or toluene).

[0104] According to Scheme 9, compounds of formula I can also beprepared from compounds of formula 17 (prepared using the methodsapplicable to the synthesis of compounds of formula I), where P is H oran appropriate amino protecting group. Such groups, known in the art oforganic synthesis for the protection of amines, include those listed in“Protective Groups in Organic Synthesis”, by Greene and Wuts [John Wiley& Sons, NY, 1991]. Examples of amine protecting groups include, but arenot limited to, acyl types (such as formyl, trifluoroacetyl, phthalyl,and p-toluenesulfonyl), carbamate types (such as benzyloxycarbonyl,t-butoxycarbonyl, 9-fluorenymethyloxycarbonyl, allyloxycarbonyl, and2,2,2-trichloroethyloxycarbonyl), alkyl types (such as benzyl andtriphenylmethyl). Reacting compounds of formula 17 with a halogenatingagent provides compounds of formula 18 where X is Br, Cl, or I.Compounds of formula 18 react with a compound of formula R⁴M (where M isalkali metal, ZnCl, ZnBr, MgBr, MgCl, MgI, CeCl₂, CeBr₂, copper halides,B(OH)₂, B(O-lower alkyl)₂, or Sn(lower alkyl)₃) in the presence orabsence of an organometallic catalyst in the presence or absence of abase in an inert solvent at temperatures ranging from −100° C. to 200°C. to give compounds of formula I (or their N-protected forms which canthen be deprotected). Similar conditions have been described in WO98/54093. Those skilled in the art will recognize that the reagents R⁴Mmay be generated in situ. Organometallic catalysts include but are notlimited to, palladium phosphine complexes (such as Pd(PPh₃)₄), palladiumhalides or alkanoates (such as PdCl₂(PPh₃)₂ or Pd(OAc)₂), or nickelcomplexes (such as NiCl₂(PPh₃)₂). Bases may include, but are not limitedto, alkali metal alkoxides (1-6 carbons) (preferably sodium methoxide,sodium ethoxide, or sodium tert-butoxide), alkali metal carbonates orbicarbonates, alkali metal hydroxides, alkali metal phosphates, ortrialkylamines (preferably N,N-di-isopropyl-N-ethyl amine ortriethylamine). Inert solvents may include, but are not limited to,lower alkanenitriles (1-6 carbons) (preferably acetonitrile), water,dialkyl ethers (preferably diethyl ether), cyclic ethers (preferablytetrahydrofliran or 1,4-dioxane), N,N-dialkylformamides (preferablydimethyl formamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one),dialkylsulfoxides(preferably dimethylsulfoxide), aromatic hydrocarbons(preferably benzene or toluene).

[0105] As shown in Scheme 10, compounds of formula 22 may be obtainedfrom compounds of formula 20, where R⁴ is defined as above. Compounds offormula 20 are reacted with compounds of formula R³—C═OR^(c), where R³is defined above and R^(c) is halogen, cyano, lower alkoxy (1-6carbons), or lower alkanoyloxy (1-6 carbons), in the presence of a basein an inert solvent at reaction temperatures ranging from −78° C. to200° C. to afford compounds of formula 21. Bases may include, but arenot limited to, alkali metal hydrides (preferably sodium hydride),alkali metal alkoxides (1-6 carbons) (preferably sodium methoxide,sodium ethoxide, or sodium tert-butoxide), alkaline earth metalhydrides, alkali metal dialkylamides (preferably lithiumdiisopropylamide), alkali metal carbonates, alkali metal hydroxides,alkali metal bis-(trialkylsilyl)amides (preferably lithium or sodium(trimethylsilyl)amide), trialkylamines (preferablyN,N-di-isopropyl-N-ethyl amine or triethylamine), bicyclic amidines(preferably DBU), or heteroaromatic amines (preferably pyridine). Inertsolvents may include, but are not limited to, alkyl alcohols (1-8carbons) (preferably methanol, ethanol, or tert-butanol), loweralkanenitriles (1-6 carbons) (preferably acetonitrile), water, dialkylethers (preferably diethyl ether), cyclic ethers (preferablytetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferablydimethyl formamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one),dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons(preferably benzene or toluene). Alternatively, compounds of formula 20may be reacted with a solvent of formula R³—C═O—R^(c), where R³ isdefined above and R^(c) is lower alkoxy (1-6 carbons), in the presenceof an alkali metal (preferably sodium) at reaction temperatures rangingfrom −78° C. to 200° C. to afford compounds of formula 21. Compounds offormula 21 may be reacted with hydrazine (hydrate or hydrochloride salt)in an inert solvent, at reaction temperatures ranging from 0°C. to 200°C., preferably 70° C. to 150° C., to afford compounds of formula 22.Inert solvents may include, but are not limited to, water, loweralkanoic acids (preferably formic, acetic, or trifluoro acetic acid),alkyl alcohols (1-8 carbons) (preferably methanol or ethanol), loweralkanenitriles (1-6 carbons) (preferably acetonitrile), cyclic ethers(preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides(preferably dimethyl formamide), N,N-dialkylacetamides (preferablydimethyl acetamide), cyclic amides (preferablyN-methylpyrrolidin-2-one), dialkylsulfoxides (preferablydimethylsulfoxide), aromatic hydrocarbons (preferably benzene ortoluene).

[0106] Alternatively, compounds of formula 21 can be obtained, asillustrated in Scheme 11, by first reacting compounds of formula 24 withdialkyl formamide dialkyl acetal of formula (R^(d)R^(e))N—CH(OR^(f))₂where R^(d), R^(e), and R^(f) are each or independently C₁-C₆ loweralkyl (preferably methyl) in the presence or absence of an inert solventat reaction temperatures ranging from 0° C. to 250° C., preferablybetween 70° C. and 150° C. to provide compounds of formula 25. Inertsolvents may include, but are not limited to, lower alkanenitriles (1-6carbons) (preferably acetonitrile), dialkyl ethers (preferably diethylether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane),N,N-dialkylformamides (preferably dimethyl formamide),N,N-dialkylacetamides (preferably dimethyl acetamide), cyclic amides(preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferablydimethylsulfoxide), aromatic hydrocarbons (preferably benzene ortoluene), or haloalkanes with 1-10 carbons and 1-10 halogens (preferablydichloromethane). Compounds of formula 25 can be reacted withhydroxylamine salt (preferably hydrochloride) in the presence or absenceof an inert solvent at reaction temperatures ranging from 0° C. to 250°C., preferably between 70° C. and 200° C. to provide oxazoles of formula26. Inert solvents may include, but are not limited to, alkyl alcohols(1-8 carbons) (preferably methanol, ethanol, or tert-butanol), loweralkanenitriles (1-6 carbons) (preferably acetonitrile), water, dialkylethers (preferably diethyl ether), cyclic ethers (preferablytetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferablydimethyl formamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one),dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons(preferably benzene or toluene). Oxazole intermediates of formula 26 canbe reacted with a base in the presence or absence of an inert solvent atreaction temperatures ranging from 0° C. to 200° C. Bases may include,but are not limited to, alkali hydroxides (preferably sodium orpotassium hydroxide), alkali metal hydrides (preferably sodium hydride),alkali metal alkoxides (1-6 carbons) (preferably sodium methoxide,sodium ethoxide, or sodium tert-butoxide), alkaline earth metalhydrides, alkali metal dialkylamides (preferably lithiumdiisopropylamide), alkali metal carbonates, alkali metal hydroxides,alkali metal bis-(trialkylsilyl)amides (preferably lithium or sodium(trimethylsilyl)amide), trialkylamines (preferablyN,N-di-isopropyl-N-ethyl amine or triethylamine), bicyclic amidines(preferably DBU), or heteroaromatic amines (preferably pyridine). Inertsolvents may include, but are not limited to, alkyl alcohols (1-8carbons) (preferably methanol, ethanol, or tert-butanol), loweralkanenitriles (1-6 carbons) (preferably acetonitrile), water, dialkylethers (preferably diethyl ether), cyclic ethers (preferablytetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferablydimethyl fornamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one),dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons(preferably benzene or toluene).

EXAMPLES

[0107] The following examples are provided to describe the invention infurther details. These examples, which set forth the best mode presentlycontemplated for carrying the invention, are intended to illustrate andnot to limit the invention.

[0108] Commercial reagents were used without further purification. THFrefers to tetrahydrofuran. LDA refers to lithium diisopropylamide andDBU refers to 1,8-diazabicyclo[5.4.0]undec-7-ene. Room or ambienttemperature refers to 20° C. to 25° C. Concentration implies the use ofa rotary evaporator. TLC refers to thin layer chromatography. Massspectral data were obtained either by CI or APCI methods. Other ommonlyused abbreviations are: Ph is phenyl, Me is methyl, Et is ethyl, Pr isn-propyl, iPr is isopropyl, Bu is butyl, iBu is isobutyl (CH₂-CHMe₂),tBu is tert-butyl, cBu is cyclobutyl, Pent is n-pentyl, cPent iscyclopentyl, chex is cyclohexyl, Py is pyridyl, MeOH means methanol,EtOH means ethanol, EtOAc means ethyl acetate, Et₂O means diethyl ether,CH₂Cl₂ means methylene chloride, DMSO means dimethyl sulfoxide, NMPmeans N-methyl pyrrolidone, THF means tetrahydrofuran, DMF meansdimethyl formamide, EX means example.

[0109] The numbering system used to describe the compounds of thepresent invention is as follows:

Example 1 Preparation of7-(2-(perhydro-2H-pyran-4-ylamino)ethylamino)-2,5-dimethyl-3-(4-chloro-2,6-dimethylphenyl)-pyrazolo[1,5-a]pyrimidine Formula I where X is CH, R¹ is CH₃, R² is H, A is CH₂, B isCH₂, R3 is CH₃, R⁴ is 2,6-dimethyl-4chlorophenyl, R⁵ isperhydro-2H-pyran-4-yl

[0110] A. 4-Bromo-3,5-dimethyl chlorobenzene

[0111] Slurry 2,6-dimethyl-4chloroaniline hydrochloride (23g, 193.11g/mol) in CH₂Cl₂ (100 ml) and wash with saturated NaHCO₃ to generate thefree base. Dry over Na₂SO₄, filter and evaporate down to a violet oil.Slurry up in 120 mL 6.0 N H₂SO₄ and stir vigorously at ambienttemperature to break up larger pieces of solid. Cool to 0° C. in anice/water bath, then portionwise over 15 minutes add a clear colorlesssolution of NaNO₂ in 50 mL H₂O. Maintain temperature 15° C. over courseof addition, stirring under dry N₂. After 1 hour, carefully pour thecold reaction solution (solution A) into a second solution (solution B)containing 31.7 g CuBr in 33 mL aqueous HBr (48%) at ambienttemperature. Let stand at ambient temperature until gas evolutionceases, then heat to 110° C. under N₂ while stirring. Stir for 3 hours,then cool to rt. Extract the aqueous layer with a (2:1) mixture ofhexanes and Et₂O (2×500 mL), then dry the combined organic layers overNa₂SO₄, filter and evaporate down to a brown oil. Triturate the oil withhexanes (100 mL), filter out the remaining solids and wash with copiousamounts of hexanes. Evaporate the hexane layers to concentrate thenflush through a pad of silica to remove baseline material, using hexanesas eluent. Evaporate to a clear colorless oil (13.5g).

[0112] B. 4-Chloro-2,6-dimethyl benzaldehyde

[0113] Dissolve 4-bromo-3,5-dimethyl chlorobenzene (6.5 g) in 50 mLanhydrous THF and cool to -78° C. (dry ice/acetone) under N₂. Dropwiseover 5 minutes add a solution of butyllithium (12.50 mL, 2.5M inhexanes) to the stirring solution of aryl bromide at −78° C. After 2hours, dropwise add anhydrous DMF (5.0 mL) to the orange/red reactionsolution and allow to warm to ambient temperature overnight whilestirring under N₂. Evaporate the yellow solution down to a yellow oiland partition between H₂O (100 mL) and CH₂Cl₂ (100 mL). Extract theaqueous layer once with CH₂Cl₂, then pool the organic layers and dryover Na₂SO₄, filter and evaporate down to 5.0 g of yellow oil. Usewithout further purification. LCMS=169.6 (MEN)

[0114] C. 4-Chloro-2,6-dimethyl benzyl alcohol

[0115] Dissolve 4-chloro-2,6-dimethyl benzaldehyde (5.0 g, 168.64 g/mol)in 100 mL dry methanol. Cool to 0° C. while stirring under N₂.Portionwise add powdered NaBH₄ (0.76g, 37.85 g/mol) over 5 minutes. Stirat 0° C. for 2 hours, monitoring by TLC until aldehyde consumed, thenevaporate to a yellow oil. Add H₂O (50 mL) and bring to pH 7.0 byaddition of saturated NH₄Cl. Extract the neutral aqueous layer withCH₂Cl₂ (3×75 mL) and dry the pooled organic layers over Na₂SO₄. Filterand concentrate to a yellow oil. Flush through a pad of silica to removebaseline material, then evaporate to a yellow solid (3.0 g) which can beused without further purification. LCMS=171.6 (MH⁺), 169.6 (M⁻).

[0116] D. 4-Chloro-2,6-dimethyl phenyl acetonitrile

[0117] Dissolve 4-chloro-2,6-dimethyl benzyl alcohol (2.8g, 170.66g/mol) in CH₂Cl₂ (25 mL) and cool to 0° C. under N₂. Dropwise addthionyl chloride (2.4 mL, 3.90 g, 118.9 g/mol) in 10 mL CH₂Cl₂ whilestirring under N₂. After 2 hours, monitoring by TLC (alcohol Rf=0.35,chloride Rf=1.0; using 20% EtOAc/80% hexanes as eluent), quench thereaction carefully by addition of saturated NaHCO₃ (100 mL) and stiruntil gas evolution ceases. Separate layers, then extract the aqueouslayer with CH₂Cl₂ (100 mL). Pool the organic layers, dry over Na₂SO₄,filter and evaporate to a pale yellow oil. Take up in DMSO (25 mL), addsolid NaCN (1.25 g, 49.011 g/mol) and heat to 60° C. while stirringunder N₂. Stir 2 hours until chloride consumed (TLC; chloride Rf−1.0,nitrile Rf=0.6; using 20% EtOAc/80% hexanes as eluent), then cool to rt.Add 2.0 N NaOH (150 mL) and stir until orange precipitate forms, thenfilter and wash solid with H₂O. Dissolve solid in CH₂Cl₂, wash with H₂O,the dry over Na₂SO₄. Filter the organic layer and evaporate to an orangeoil which crystallizes upon standing at rt. (2.3 g). LCMS=180.2 (MH⁺),178.2 (M⁻).

[0118] E. 2-(4-Chloro-2,6-dimethylphenyl)-3-oxobutanenitrile

[0119] Dissolve 4-chloro-2,6-dimethyl phenyl acetonitrile (2.3 g, 179.2g/mol) in 15 mL EtOAc and add sodium metal (0.35 g, pea-sizedfragments). Heat to reflux (90° C. bath temperature) under N₂ overnight.Evaporate down to solid and slurry up in Et₂O (100 mL); stir vigorouslyto break up fragments. Filter and wash solid with copious amounts ofEt₂O. Dissolve solid in H₂O to form a clear yellow solution, and add 1.0N HCl (100 mL) to pH 1. Extract the resulting cloudy solution withCH₂Cl₂ (3×100 mL) until aqueous layer is clear. Pool and dry the organiclayers over Na₂SO₄, filter and evaporate to yellow oil (1.8g). TLC:Rf=0.2 using 20% EtOAc/80% hexanes as eluent. LCMS=222.3 (MH⁺); 220.2(M⁻).

[0120] F. 5-Amino-4-(4-chloro-2,6-dimethylphenyl)-3-methylpyrazole

[0121] Dissolve anhydrous hydrazine (0.91g, 0.90 mL) in 20 mL toluene.Add glacial acetic acid (2.25 mL) and allow to stand at ambienttemperature for 10 minutes until solution becomes cloudy white. Add asolution of 2-(4-chloro-2,6-dimethylphenyl)-3-oxobutanenitrile in 10 mLtoluene, rinsing out the ketonitrile flask with an additional 5 mLtoluene. Heat to reflux under N₂ (130° C.) with Dean-Stark trapattached. Water will begin to accumulate after 10 minutes or so. After 2hours, evaporate down and partition between 1.0 N NaOH (100 mL) andEtOAc (100 mL). Extract aqueous layer with EtOAc (2×100 mL), then poolthe organic layers and dry over Na₂SO₄. Filter and evaporate to yellowoil (1.75 g). Use without further purification. LCMS=236.5 (MH⁺); 234.5(M⁻).

[0122] G.7-Hydroxy-2,5-dimethyl-3-(4-chloro-2,6-dimethylphenyl)-pyrazolo[1,5-a]pyrimidine

[0123] Dissolve 5-amino-4-(4-chloro-2,6-dimethylphenyl)-3-methylpyrazolein 20 mL glacial acetic acid at ambient temperature, and add ethylacetoacetate (2.0 mL, 1.99 g). Heat to reflux (130° C.) under N₂overnight. Evaporate down to concentrate and add 200 mL Et2O toprecipitate out product. Stir at ambient temperature for 1 hour, thenfilter and wash the resulting white solid (1.25 g) with copious amountsof Et₂O. LCMS=302.2 (MH⁺); 300.2 (M⁻).

[0124] H. 7-Chloro-2,5-dimethyl-3-(4-chloro-2,6-dimethylphenyl)-pyrazolo[1,5-a]pyrimidine

[0125] Slurry7-hydroxy-2,5-dimethyl-3-(4-chloro-2,6-dimethylphenyl)-pyrazolo[1,5-a]pyrimidine in 10 mL POCl₃ and reflux at 130° C. under N₂. After 2 hours,monitoring by TLC (alcohol Rf=0.5, chloride Rf=1.0; EtOAc as eluent),quench the reaction carefully at ambient temperature by diluting with 50mL CH₂Cl₂ and pouring slowly into non-stirring saturated NaHCO₃. Adjuststirring speed to control rate of quenching of residual POCl₃ and stiruntil gas evolution ceases. Separate the layers and extract the aqueouslayer with CH₂Cl₂ (2×50 mnL). Pool the organic layers and dry overNa₂SO₄. Filter and evaporate to yellow oil, which is used directlywithout further purification.

[0126] I.7-(2-aminoethylamino)-2,5-dimethyl-3-(4-chloro-2,6-dimethylphenyl)-pyrazolo[1,5-a]pyrimidine

[0127] Dissolve7-chloro-2,5-dimethyl-3-(4-chloro-2,6-dimethylphenyl)-pyrazolo[1,5-a]pyrimidine in 25 mL CH₃CN, then add excess ethylenediamine (5 mL) andheat to 80° C. for 3-6 hours under N₂ with attached reflux condenser.(TLC; product diamine Rf=0.5, aryl chloride Rf=1.0; [10% (2.0M NH₃ inMeOH)/90% CH₂Cl₂] as eluent). Cool to ambient temperature and evaporateto yellow oil. Partition between CH₂Cl₂ (50 mL) and 1.0 N NaOH (50 mL),and extract aqueous layer 2×30 mL CH₂Cl₂. Pool organic layers, dry overNa₂SO₄, filter and evaporate to yellow-white foam (1.25 g). Use withoutfurther purification. LCMS=344.4 (MH⁺); 342.3 (M⁻).

[0128] J.7-(2-(perhydro-2H-pyran-4-ylamino)ethylamino)-2,5-dimethyl-3-(4-chloro-2,6-dimethylphenyl)-pyrazolo[1,5-a]pyrimidine

[0129] Dissolve7-(2-aminoethylamino)-2,5-dimethyl-3-(4-chloro-2,6-dimethylphenyl)-pyrazolo[1,5-a]pyrimidine (0.183g, 5.4×10⁴ mol, 339.2 g/mol) in dichloroethane (5 mL)and add tetrahydro4H-pyran-4-one (0.068 g, 0.060 mL, 100.12 g/mol) andsodium triacetoxyborohydride (0.172 g, 211.94 g/mol). To the resultantslurry, add glacial acetic acid (0.032 mL, 5.4×10⁻⁴ mol) and stir atambient temperature under N₂ for 3 hours. Partition between CH₂Cl₂ (3mL) and 1.0 N NaOH (10 mL), then separate the layers and chromatographthe CH₂Cl₂ layer using [10% (2.0M NH₃ in MeOH)/90% CH₂Cl₂] as eluent.Obtained 0.16 g white solid-foam upon evaporation. TLC: Rf=0.65.LCMS=422.5 (MH⁺); 420.5 (M⁻). H-NMR (CDCl₃): 6.67 (s, 2H); 5.79 (d, 1H,J=8.8 Hz); 3.98 (br. d, 2H, J=12 Hz); 3.78 (s, 3H); 3.52 (t, 2H, J=6Hz); 3.39 (br. t, 2H, J=12 Hz); 3.37 (s, 1H); 3.04 (t, 2H, J=6 Hz);2.75-2.81 (m, 2H); 2.40 (s, 3H); 2.18 (s, 3H); 2.00 (s, 6H); 1.89 (br.d, 2H, J=12 Hz); 1.47-1.53 (m, 2H).

Example 2 Preparation of7-(2-(2-(4-ethoxy-3-methoxyphenyl)ethylamino)ethylamino)-3-(2,4-dimethoxyphenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidineFormula I where X is CH, R¹ is CH₃, R² is H, A is CH₂, B is CH₂, R³ isCH₃, R⁴ is 2,4-dimethoxyphenyl, R⁵ is2-(4-ethoxy-3-methoxyphenyl)ethylamino)ethyl

[0130] A. (3E)-3-(2,4-dimethoxyphenyl)-4-(dimethylamino)but-3-en-2-one

[0131] Dissolve 1-(2,4-dimethoxyphenyl)acetone (1.0 g, 5.15 mmol, 194.23g/mol) in DMF-diethyl acetal (4.5 mL, 25.7 mmol, 147.22 g/mol) and stirunder N₂ at 100° C. overnight. TLC using 20% EtOAc/80% hexanes; (ketoneRf=0.25, product Rf=0.0). Evaporate to thick oil, dissolve in EtOAc (25mL) and wash with H₂O (3×25 mL). Extract pooled H₂O layers with EtOAc.Dry pooled organic layers over Na₂SO₄, filter and evaporate to thick oilwhich solidifies upon standing at ambient temperature (0.98 g). Usewithout further purification. LCMS=250.2 (NH⁺); 248.2 (M⁻).

[0132] B. 4-(2,4-Dimethoxyphenyl)-5-methyl-isoxazole

[0133] Dissolve(3E)-3-(2,4-dimethoxyphenyl)-4-(dimethylamino)but-3-en-2-one (5.1 g,20.6 mmol) in EtOH (50 mL) and add NH₂OH.HCl (3.05 g, 44.0 mmol). Heatto reflux under N₂ for 20 minutes. Cool and evaporate to red-brown oil.Dissolve in CH₂Cl₂, dry over Na₂SO₄, filter and concentrate to red-brownoil (4.4 g). Use without further purification. LCMS=220.2 (MH⁺); 218.2(M⁻).

[0134] C. 2-(2,4-Dimethoxyphenyl)-3-oxobutanenitrile.

[0135] Slurry 4-(2,4-dimethoxyphenyl)-5-methyl-isoxazole (4.4 g) in 1.0N NaOH (35 nmL) and add 35 mL MeOH to dissolve. Heat at 60° C. under N₂for 1 hour, then cool to clear brown solution. Add 1.0 N HCl to acidifyto pH 1, then filter the resulting white solid precipitate. Dissolvesolid in EtOAc, dry over Na₂SO₄, filter and concentrate to red oil. Usewithout further purification. LCMS=220.2 (MH⁺); 218.2 (M⁻).

[0136] D. N-(4-Ethoxy-3-methoxy-phenethyl)-ethylenediamine.

[0137] Dissolve 4-ethoxy-3-methoxy-phenyl acetic acid (26 g, 119 mol) indichloroethane (300 mL, anhydrous) and cool to 0° C. Dropwise add oxalylchloride (130 mL, 2.0 M in CH₂Cl₂) and DMF (2 mL), then allow to warm toambient temperature overnight. Evaporate down and chase with CH₂Cl₂,then evaporate to a tan oil. Dissolve in 200 mL dichloroethane and coolto 0° C. while stirring under N₂. Dropwise, over 45 minutes, add asecond solution of N-tBOC-ethylenediamine (20 g) and triethylamine (20mL) in 100 mL dichloroethane. Partition between CH₂Cl₂ (500 mL) and 1.0N HCl (200 mL), then separate the layers and wash the organic layer with1.0 N HCl (200 mL). Wash the organic layer with saturated K₂CO₃ (2 x 200mL), then dry the CH₂Cl₂ layer over Na₂SO₄, filter and evaporate to tansolid. Triturate with 200 mL Et₂O and stir vigorously to fragment solid,then filter and wash copiously with Et₂O to obtain 20.5 g white solid.Dissolve white solid (3.0 g, 8.52 mmol) in 10 mL (1:1 trifluoraceticacid:CH₂Cl₂) and stir at ambient temperature 1 hour. Evaporate down andpartition between CH₂Cl₂ (25 mL) and 1.0 N NaOH (25 mL), then separatethe layers and extract the aqueous layer with CH₂Cl₂ (25 mL). Pool theorganic layers, dry over Na₂SO₄, filter and evaporate to a white solid(1.75 g).

[0138] E.7-(2-(2-(4-ethoxy-3-methoxyphenyl)ethylamino)ethylamino)-3-(2,4-dimethoxyphenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine.

[0139] Dissolve 7-chloro-2,5-dimethyl-3-(2,4-dimethoxyphenyl)-pyrazolo[1,5-a]pyrimidine (prepared from2-(2,4-dimethoxyphenyl)-3-oxobutanenitrile according to the methods ofEXAMPLE 1 F, G and H) (0.2 g, 6.31×10mol) in dichloroethane (10 mL),then add the N-(4-ethoxy-3 -methoxy-phenethyl)-ethylenediamine from stepD (0.10 g, 4.2×10⁴ mol) and diisopropylethylamine (0.1 mL, 6×10⁻⁴ mol)and stir under N₂ at 80° C. overnight. Wash the organic layer withsaturated NaHCO₃ (10 mL), then evaporate the organic layer down to ayellow oil. Chromatograph using [10% (2.0 M NH₃ in MeOH)/90% CH₂Cl₂] andevaporate to obtain 50 mg pale yellow solid. LCMS=520.3 (MH⁺); 518.3(M⁻). H-NMR (CDCl₃): 7.35 (d, 1H, J=8.4 Hz); 6.71-6.8 (m, 3H); 6.56-6.61(m, 2H); 6.47 (t, 1H, J=5.6 Hz); 5.75 (s, 1H); 4.05 (quart., 2H, J=6.8Hz); 3.82-3.88 (m, 5H); 3.77 (s, 3H); 3.42 (quart., 2H, J=5.6 Hz); 2.97(t, 2H, J=6 Hz); 2.90 (t, 2H, J=6 Hz); 2.76 (t, 2H, J=7.2 Hz); 2.44 (s,3H); 2.35 (s, 3H)1.43 (t, 3H, J=6.8 Hz).

Example 3 Preparation of7-(2-(perhydro-2H-pyran-4-ylamino)ethylamino)-2,5-dimethyl-3-(2,6-dimethyl-4-methoxyphenyl)-pyrazolo[1,5-a]pyrimidine Formula I where X is CH, R¹ is CH₃, R² is H, A is CH₂, B isCH₂, R³ is CH₃, R⁴ is 2,4-dimethyl-4-methoxyphenyl, R⁵ isperhydro-2H-pyran-4-yl

[0140] A. 4-Methoxy-2,6-dimethyl phenyl acetonitrile

[0141] Dropwise add a solution of chlorotrimethylsilane (20 mL) inCH₂Cl₂ (40 mL) to a stirred solution cooled to 0° C. of4-methoxy-2,6-dimethyl benzyl alcohol (approx. 74 mmol) in 300 mLCH₂Cl₂. Solution changes color from colorless to yellow and then topurple over the course of the reaction. After 2 hours, monitoring by TLC(alcohol Rf=0.25, chloride Rf=0.95; using 20% EtOAc/80% hexanes aseluent), evaporate down to a yellow oil. Dissolve in dry DMF (50 mL) andcool to 0° C. under N₂. Add freshly ground NaCN (7.0 g) portionwise over5 minute (exothermic) to the stirring reaction, forming a yellow/whiteslurry. Stir for 5-8 hours at 0° C. until no starting material remains,as determined by TLC (nitrile Rf=0.5; using 20% EtOAc/80% hexanes aseluent). Partition the reaction solution between EtOAc (100 mL) and 0.1N NaOH (300 mL). Dry the EtOAc layer over Na2SO4, filter and evaporateto yellow oil. Chromatograph in 10% EtOAC/90% hexanes on silica toremove residual chloride and evaporate to 2.1 g yellow solid; clean byTLC. LCMS=176.5 (MH⁺), 174.4 (M⁻).

[0142] B.7-(2-(Perhydro-2H-pyran-4-ylamino)ethylamino)-2,5-dimethyl-3-(2,6-dimethyl-4-methoxyphenyl)-pyrazolo[1,5-a]pyrimidine

[0143] 7-(2-(Perhydro-2H-pyran-4-ylamino)ethylamino)-2,5-dimethyl-3-(2,6-dimethyl-4-methoxyphenyl)-pyrazolo[1,5-a] pyrimidine is obtainedfrom 4-methoxy-2,6-dimethyl phenyl acetonitrile using the proceduresdescribed in EXAMPLE 1 E, F, G, H, I, J.

Example 4 Preparation of7-(2-(perhydro-2H-pyran-4-ylamino)ethylamino)-2-trifluoromethyl-5-methyl-3-(2,4-dichlorophenyl)-pyrazolo[1,5-a]pyrimidine Formula I where X is CH, R¹ is CH₃, R² is H, A is CH₂, B isCH₂, R³ is CF₃, R⁴ is 2,4-dichlorophenyl, R⁵ is perhydro-2H-pyran-4-yl

[0144] A. 2-(2,4-Dichlorophenyl)-4,4,4-trifluoro-3-oxobutanenitrile

[0145] Slurry 2,4-dichlorophenylacetonitrile (I) (5.0 g, 26.9 mmol,186.04 g/mol) in ethyl trifluoroacetate (6.4 mL, 7.6 g, 142.08 g/mol)and add 20 mL anhydrous THE. Portionwise at ambient temperature add NaH(1.88 g, 47.1 mmol, 60% in mineral oil) over 5 minutes. Heat reaction toreflux (90° C. bath temperature) overnight. Evaporate to thick red-brownoil and partition between Et₂O (100 mL) and H₂0 (60 mL). Separate layersand extract H₂0 with Et₂O (2×75 mL). Acidify the aqueous layer with 1.0N HCl to pH 1 (becomes cloudy white suspension) and extract aqueouslayer with CH₂Cl₂ (3×100 mL). Dry pooled CH₂Cl₂ layers over Na₂SO₄,filter and concentrate to yellow oil (7.5 g, 26.5 mmol). Use withoutfurther purification. LCMS=281.9 (MH⁺); 279.8 (M⁻).

[0146] B.7-(2-(Perhydro-2H-pyran-4-ylamino)ethylamino)-2-trifluoromethyl-5-methyl-3-(2,4-dichlorophenyl)-pyrazolo[1,5-a]pyrimidine

[0147] 7-(2-(Perhydro-2Hpyran-4-ylamino)ethylamino)-2-trifluoromethyl-5-methy1-3-(2,4-dichlorophenyl)-pyrazolo[ 1,5-a] pyrimidine is obtainedfrom 2-(2,4-dichlorophenyl) 4,4,4-trifluoro-3-oxobutanenitrile using theprocedures described in EXAMPLE 1 F, G, H, ,J.

Example 5 Preparation of7-(2-(2-(4-methoxyphenyl)ethylamino)ethylamino)-3-(2,4,6-trimethylphenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidineFormula I where X is CH, R¹ is CH₃, R² is H, A is CH₂, B is CH₂, R³ isCH₃, R⁴ is 2,4,6-trimethylphenyl, R⁵ is2-(4-methoxyphenyl)ethylamino)ethyl

[0148] A.N-(3-(2,4,6-trimethylphenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7yl)-2-(4-methoxyphenyl)acetamide

[0149] Dissolve 7-chloro-2,5-dimethyl-3-(2,4,6-trimethylphenyl)-pyrazolo[1,5-a]pyrimidine (0.26 g, 8.69×10⁻⁴mol) in 2 mL N-methylpyrrolidine, and addN-(2-aminoethyl)-2-(4-methoxyphenyl)acetamide (0.75 g, 3.6 mmol). Heatto 80° C. overnight under N₂. Partition between EtOAc (50 mL) and H₂O(50 mL), then separate layers and wash EtOAC layer successively with 0.1N NaOH (25 mL), H₂O (25 mL), and brine. Pool aqueous layers and extractwith EtOAc (25 mL). Pool EtOAc layers, dry over Na₂SO₄, filter andconcentrate to yellow oil. Chromatograph on silica gel eluting withEtOAc and evaporate to obtain 0.30 g ofN-(3-(2,4,6-trimethylphenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7yl)-2-(4-methoxyphenyl)acetamideas a clear pale yellow oil. LCMS=472.3 (MH⁺); 470.2 (M⁻). ¹H-NMR(CDCl₃): 7.10 (d, 2H, J=10.2 Hz); 6.39 (s, 2H); 6.81 (d, 2H, J=10.2 Hz);6.46 (t, 1H, J=6.0 Hz); 6.16 (t, 1H, J=6.0 Hz); 5.79 (s, 1H); 3.76 (s,3H); 3.45-3.50 (mn, 6H); 2.38 (s, 3H); 2.30 (s, 3H); 2.20 (s, 3H); 2.02(s, 6H).

[0150] B.7-(2-(2-(4-methoxyphenyl)ethylamino)ethylamino)-3-(2,4,6-trimethylphenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine

[0151] DissolveN-(3-(2,4,6-trimethylphenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7yl)-2-(4-methoxyphenyl)acetamide (0.15 g, 3.2×10⁻⁴ mol) in 5 mLanhydrous THF and stir under N₂. Add borane-dimethylsulfide complex(0.25 mL, 10.0 M in THF) and heat to reflux overnight. Quench by carefuladdition of MeOH until gas evolution ceases, then evaporate to oil. AddHCl in Et₂O (2 TnL, 1.0 M) and MeOH to solubilize (5 mL), then reflux 1hour and evaporate. Dissolve in CH₂Cl₂ (20 mL) and wash with saturatedNaHCO₃ (20 mL). Evaporate CH₂Cl₂ layer and chromatograph on silica geleluting with EtOAc (Rf=0.15), then evaporate down to a clear oil (0.10g). LCMS=458.3 (MH+), 456.4 (M⁻). ¹H-NMR (CD₃Cl): 7.13 (d, 2H, J=8.8Hz); 6.94 (s, 3H); 6.84 (d, 2H, J=8.8 Hz); 6.57 (t, 1H, J=5.6 Hz); 5.77(s, 1H); 3.78 (s, 3H); 3.44 (quartet, 2H, J=5.6 Hz); 3.00 (t, 2H, J=6.0Hz); 2.92 (t, 2H, J=6.8 Hz); 2.78 (t, 2H, J=6.8 Hz); 2.41 (s, 3H); 2.31(s, 3H); 2.22 (s, 3H); 2.01 (s, 6H).

[0152] Alternatively, the reduction can be carried out as follows:dissolveN-(3-(2,4,6-trimethylphenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl)-2-(4-methoxyphenyl)acetamide(0.15g, 3.2×10⁻⁴ mol) in 5 mL anhydrous THF. Add a fresh solution ofalane·dimethylethylamine complex in toluene (2.25 mL, 9.6×10⁻⁴ mol) andheat to 50° C. overnight under dry N₂. Quench reaction by addition ofsolid Na₂CO₃.10H₂O (0.5 g) and stir vigorously until gas evolutionceases. Filter through celite to remove solid and evaporate the filtratedown to a clear pale yellow oil. Chromatograph on silica gel elutingwith EtOAc (Rf=0.15), then evaporate down to a clear oil (0.10 g).

Example 6 Preparation of7-(2-(2-(4-ethoxy-3-methoxyphenyl)ethylamino)ethylamino)-3-(2,4,6-trimethylphenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidineFormula I where X is CH, R¹ is CH₃, R² is H, A is CH₂, B is CH₂, R³ isCH₃, R⁴ is 2,4,6-trimethylphenyl, R⁵ is2-(4-ethoxy-3-methoxyphenyl)ethylamino)ethyl

[0153] A.N-(3-(2,4,6-trimethylphenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl)-2-(4-ethoxy-3-methoxyphenyl)acetamide

[0154] Dissolve7-(2-aminoethylamino)-2,5-dimethyl-3-(2,4,6-trimethylphenyl)-pyrazolo[1,5-a]pyrimidine (91 mg, 2.8×10⁻⁴ mol) in N-methyl pyrrolidine (2 mL) and add2-(4-ethoxy-3-methoxyphenyl)acetic acid (65 mg, 3.1×10⁻⁴ mol). Addtriethylamine (85 mg, 0.117 mL, 8.46×10⁴ mol) and BOP-Cl (0.15 g,3.4×10⁻⁴ mol), then stir at ambient temperature under N₂ overnight.Partition between H₂O (10 mL) and EtOAc (10 mL), then separate layersand wash EtOAc layer with 1.0 N NaOH (10 nmL). Dry the EtOAc layer overNa₂SO₄, filter and evaporate to oil. Use without further purification.LCMS=516.3 (MH⁺); 514.2 (M⁻).

[0155] Alternatively,N-(2-aminoethyl)-2-(4-ethoxy-3-methoxyphenyl)acetamide can be preparedas follows: dissolve 2-(4-ethoxy-3-methoxyphenyl)acetic acid in (26 g,119 mol) in dichloroethane (300 mL, anhydrous) and cool to 0° C.Dropwise add oxalyl chloride (130 mL, 2.0 M in CH₂Cl₂) and DMF (2 mL),then allow to warm to ambient temperature overnight. Evaporate down andchase with CH₂Cl₂, then evaporate to a tan solid. Dissolve a portion ofthe tan solid acid chloride (80 mg, 3.5×10⁻⁴ mol) in N-methylpyrrolidine (2 mL) and cool to 0° C. Add7-(2-aminoethylamino)-2,5-dimethyl-3-(2,4,6-trimethylphenyl)-pyrazolo[1,5-a]pyrimidine (100 mg, 3.1×10⁻⁴ mol) and triethylamine (85 mg, 0.117 mL,8.46×10⁻⁴ mol), then stir at ambient temperature under N₂ overnight.Partition between H₂O (10 mL) and EtOAc (10 mL), then separate layersand wash EtOAc layer with 1.0 N NaOH (10 mL). Dry the EtOAc layer overNa₂SO₄, filter and evaporate to oil. Use without further purification.

[0156] B7-(2-(2-(4-Ethoxy-3-methoxyphenyl)ethylamino)ethylamino)-3-(2,4,6-trimethylphenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine.

[0157] Reduction ofN-(3-(2,4,6-trimethyiphenyl)-2,5-dimethyi-pyrazolo[1,5-a]pyrimidin-7-yl)-2-(4-ethoxy-3methoxyphenyl)acetaxnidewith borane-dimethylsulfide complex, according, to the procedure ofEXAMPLE 5, yields 7-(2-(2-(4-ethoxy-3pyrazolo[1,5-a]pyrimidine.LCMS=502.3 (MH⁺); 500.4 (M⁻).

Example 7 Preparation of7-(2-(perhydro-2H-pyran-4-yiamino)ethyiamino)-2,5-dimethyi-3-(4methoxy-2,6-dimethyiphenyi)-[1,5-a]-pyrazolo-1,3,5-triazine.Formula I where X is N, R¹ is CH₃, R² is H, A is CH₂, B is CH₂, R³ isCH₃, R⁴ is 2,6-dimethyl-4-methoxyphenyl, R⁵ is perhydro-2H-pyran-4-yl

[0158] A. (Iminoethyl) [4-(4-methoxy-2,6-dimethylphenyl)-3-methylpyrazol-5-yl]amine acetate salt.

[0159] To a solution of5-amino-4-(4-methoxy-2,6-dimethylphenyl)-3-methylpyrazole (1.89 g)(prepared from 4-methoxy-2,6-dimethyl benzaldehyde according to Example1 C—F) in acetonitrile (30 mL) add ethylacetimidate (free base, 1.8 mL)followed by acetic acid (0.47 mL). Collect the precipitate that formedupon stirring overnight by filtration. Wash the solid with dry ether anddry to afford 2.61 g of(iminoethyl)[4-(4-methoxy-2,6-dimethylphenyl)-3-methylpyrazol-5-yl]amineacetate salt as a white powder.

[0160] B.2,6-Dimethyl-7-(2,6-dimethyl-4-methoxyphenyl)-3H-[1,5-c]-pyrazolo-1,3,5-triazin-4-one.

[0161] Add sodium pieces (1.81 g) to a flask containing anhydrousethanol and equipped with a reflux condenser. Allow the mixture to stiruntil all the sodium is consumed and then add the amidine (2.61 g as theacetate salt) from step A in one portion. Add diethyl carbonate (7.6 mL)and reflux the mixture overnight. Concentrate the mixture under reducedpressure, dissolve the residue in water (75 mL) and adjust the pH to 5with 3N HCl. Extract the aqueous mixture with ethyl acetate and wash theextracts with brine, dry over anhydrous sodium sulfate, and concentratein vacuo to obtain a foam. Stir the residue with hexanes for 20 minutesand collect the solid by filtration, then wash with hexanes to obtain2.01 g of2,6-dimethyl-7-(2,6-dimethyl-4-methoxyphenyl)-3H-[1,5-c]-pyrazolo-1,3,5-triazin-4-oneas a yellow powder: MS 299 (M+H).

[0162] C. 4-Chloro-2,6-dimethyl-7-(2,6-dimethyl-4-methoxyphenyl)[1,5-a]-pyrazolo-1,3,5-triazine.

[0163] Dissolve2,6-dimethyl-7-(2,6-dimethyl-4-methoxyphenyl)-3H-[1,5-c]-pyrazolo-1,3,5-triazin-4-onefrom step B (1 g) in POCl₃ (50 mL) and add N,N-dimethylaniline (0.55mL). Reflux the reaction mixture under a dry nitrogen atmosphere for 18hat which time concentrate the mixture under reduced pressure. Dissolvethe residue in ethyl acetate and wash with a saturated aqueous NaHCO₃solution, then with brine. Dry the organic layer over anhydrous sodiumsulfate, filter and concentrate under reduced pressure to obtain4-chloro-2,6-dimethyl-7-(2,6-dimethyl-4-methoxyphenyl)[1,5-a]-pyrazolo-1,3,5-triazine as a dark oil. MS 317 (M+H).

[0164] D.2,6-Dimethyl-7-(2,6-dimethyl-4-methoxyphenyl)-4-(2-aminoethyl)amino-[1,5-a]-pyrazolo-1,3,5-triazine.

[0165] Dissolve 4-chloro-2,6-dimethyl-7-(2,6-dimethyl-4-methoxyphenyl)[1,5-a]-pyrazolo-1,3,5-triazine in dry toluene (10 mL) to form a stocksolution of the chloride (0.34 M). Add a portion of this solution (8 mL)dropwise into a stirring solution of ethylenediamine (3.6 mL) inacetonitrile (50 mL) which is heated to 60° C. After 3h at 60° C., coolthe solution, concentrate under reduced pressure, dilute with 10% NaOHand extract with ethyl acetate. Wash the combined extracts with brine,dry over anhydrous sodium sulfate and concentrate under reduced pressureto obtain a yellow residue. Triturate the residue with 20% ethylacetate/hexanes and collect the resulting solid by filtration to obtain0.72 g of2,6-dimethyl-7-(2,6-dimethyl-4-methoxyphenyl)-4-(2-aminoethyl)amino-[1,5-a]-pyrazolo-1,3,5-triazineas a yellow solid: MS 341 (M+H).

[0166] E.2,6-Dimethyl-7-(2,6-dimethyl-4-methoxyphenyl)-4-(2-(perhydro-2H-pyran-4-ylamino)ethylamino)-[1,5-a]-pyrazolo-1,3,5-triazine.

[0167] Dissolve2,6-dimethyl-7-(2,6-dimethyl-4-methoxyphenyl)4(2-aminoethyl)amino-[1,5a]-pyrazolo-1,3,5-triazinefrom step D (0.211 g) in dry dichloroethane (15 mL) and addtetrahydro-4-H-pyran-4-one (57 μL). Add acetic acid (35 μL) followed bysodium triacetoxyborohydride (0.184 g) and stir the resultinghomogeneous mixture overnight at ambient temperature. Dilute thereaction mixture with 4 volumes of dichloromethane, wash with brine, dryover anhydrous sodium sulfate, and concentrate under reduced pressure toobtain a yellow solid. Purify using preparative thin-layerchromatography [10% MeOH(2N NH₃)/CH₂Cl₂] to obtain2,6-dimethyl-7-(2,6-dimethyl-4-methoxyphenyl)-4-(2-(perhydro-2H-pyran-4-ylamino)ethylamino)-[1,5-a]-pyrazolo-1,3,5-triazine(0.165 g) as a light-yellow solid: MS 425 (M+H).

Example 8 Preparation of2-[(2-{[7-(2,6-dichloro-4-ethoxyphenyl)-2,6-dimethylpyrazolo[1,5-a]1,3,5-triazin-4-yl]amino}ethyl)amino]-2-methylpropan-1-ol Formula I where X is N, R¹ is CH₃, R² is H, A is CH₂, B is CH₂, R³is CH₃, R⁴ is 2,6-dichloro-4-ethoxyphenyl, R⁵ is C(CH₃)₂CH₂OH

[0168] A.Iminoethyl)[4-(4-ethoxy-2,6-dichlorophenyl)-3-methylpyrazol-5-yl]amineacetate salt.

[0169] To a solution of5-amino-4-(4-ethoxy-2,6-dichlorophenyl)-3-methylpyrazole (4.8 g)(prepared from 4-ethoxy-2,6-dichloro benzaldehyde according to Example 1C-F) in acetonitrile (50 mL) add ethylacetimidate (free base, 2.3 mL)followed by acetic acid (0.96 mL). Collect the precipitate that formedupon stirring overnight by filtration. Wash the solid with dry ether anddry to afford 5.02 g of(iminoethyl)[4-(4-ethoxy-2,6-dichlorophenyl)-3-methylpyrazol-5-yl]amineacetate salt as a white powder.

[0170] B.2,6-Dimethyl-7-(2,6-dichloro-4-ethoxyphenyl)-3H-[1,5-c]-pyrazolo-1,3,5-triazin-4-one.

[0171] Add sodium pieces (2.98 g) to a flask containing anhydrousethanol and equipped with a reflux condenser. Allow the mixture to stiruntil all the sodium is consumed and then add the amidine (5.02 g as theacetate salt) from step A in one portion. Add diethyl carbonate (12.6mL) and reflux the mixture for four hours. Concentrate the mixture underreduced pressure, dissolve the residue in water (75 mL) and adjust thepH to 5 with 3N HCl. Extract the aqueous mixture with ethyl acetate andwash the extracts with brine, dry over anhydrous sodium sulfate, andconcentrate in vacuo to obtain a foam. Stir the residue with hexanes for20 minutes and collect the solid by filtration, then wash with hexanesto obtain 4.41 g of2,6-dimethyl-7-(2,6-dichloro-4-ethoxyphenyl)-3H-[1,5-c]-pyrazolo-1,3,5-triazin-4-oneas a beige solid: MS 353 (M+H).

[0172] C. 4-Chloro-2,6-dimethyl-7-(2,6-dichloro4-ethoxyphenyl)[1,5-a]-pyrazolo-1,3,5-triazine.

[0173] Dissolve2,6-dimethyl-7-(2,6-dichloro-4-ethoxyphenyl)-3H-[1,5-c]-pyrazolo-1,3,5-triazin-4-onefrom step B (1.05 g) in POCl₃ (50 mL) and add 2,6-lutidine (0.45 mL).Reflux the reaction mixture under a dry nitrogen atmosphere for 48 h andthen concentrate the mixture under reduced pressure. Dissolve theresidue in ethyl acetate and wash with a saturated aqueous NaHCO₃solution, then with brine. Dry the organic layer over anhydrous sodiumsulfate, filter and concentrate under reduced pressure to obtain an oilwhich crystallizes upon standing. Wash the solid with hexanes to removeresidual 2,6-lutidine and collect the solid on a sintered glass funnelyielding 4-chloro-2,6-dimethyl-7-(2,6-dichloro-4-ethoxyphenyl)[1,5-a]-pyrazolo-1,3,5-triazine. MS 372 (M+H).

[0174] D.2,6-Dimethyl-7-(2,6-dichloro-4-ethoxyphenyl)-4-(2,2-dimethoxyethyl)amino-[1,5-a]-pyrazolo-1,3,5-triazine.

[0175] Dissolve the product from step C in dry acetonitrile and then add2.1 equivalents of aminoacetaldehyde dimethyl acetal. Heat the solutionto 60° C. and stir under a dry nitrogen atmosphere for 2-6 hours. Removethe solvent under reduced pressure, dilute with 10% NaOH and extractwith ethyl acetate. Wash the combined extracts with brine, dry overanhydrous sodium sulfate and concentrate under reduced pressure toobtain a yellow oil which crystallizes upon standing. The product,2,6-dimethyl-7-(2,6-dichloro-4-ethoxyphenyl)-4-(2,2-dimethoxyethyl)amino-[1,5-a]-pyrazolo-1,3,5-triazine,is used without further purification. MS (M+H).

[0176] B.2-{[7-(2,6-dichloro-4-ethoxyphenyl)-2,5,6-trimethyl-3-pyrazolino[2,3-a]1,3,5-triazin-4-yl]amino}ethanal.

[0177] Dissolve the product obtained from step D in neat trifluoroaceticacid (25 mL). After allowing the mixture to stand at ambient temperaturefor 0.5 h, concentrate the mixture under reduced pressure. Add saturatedaqueous sodium bicarbonate and stir the resulting heterogeneous mixturefor 0.5 h. Extract the aqueous solution with EtOAc, wash the EtOAcextracts with brine and then dry over anhydrous sodium sulfate.Evaporation of the solvent under reduced pressure yields the aldehyde asan off-white foam. ¹H NMR (CDC13): δ 9.79 (s, 1H, CHO).

[0178] F.2-[(2-{[7-(2,6-dichloro-4-ethoxyphenyl)-2,6-dimethylpyrazolo[1,5-a]1,3,5-triazin-4-yl]amino}ethyl)amino]-2-methylpropan-1-ol.

[0179] Dissolve the aldehyde (62 mg, 0.16 mmol) obtained from step E indry dichloroethane (4 mL). Add 1.1 equivalents of2-amino-2-methyl-1-propanol (15 μL) followed by 1 equivalent of aceticacid. After the addition of sodium triacetoxyborohydride (1.4 eq), stirthe solution at ambient temperature for several hours. Dilute thereaction mixture with 4 volumes of methylene chloride then wash themixture with brine (1×), dry over anhydrous Na2SO4. Concentrate underreduced pressure. Preparative thin layer chromatography [10% MeOH(2NNH₃)/CH₂Cl₂)] of the oily residue yields2-[(2-{[7-(2,6-dichloro-4-ethoxyphenyl)-2,6-dimethylpyrazolo[1,5-a]1,3,5-triazin-4-yl]amino}ethyl)amino]-2-methylpropan-1-ol.

[0180] The preparation of the compounds of the present invention by theabove-mentioned methods is illustrated further by the followingexamples, delineated in the TABLE which are not to be construed aslimiting the invention in scope or spirit to the specific procedures andcompounds described in them. Commonly used abbreviations are: Ph isphenyl, Me is methyl, Et is ethyl, Pr is n-propyl, iPr is isopropyl, cPris cyclopropyl, Bu is butyl, iBu is isobutyl (CH₂-CHMe₂), tBu istert-butyl, cBu is cyclobutyl, Pent is n-pentyl, cPent is cyclopentyl,chex is cyclohexyl, Py is pyridyl, Bn is benzyl (CH₂Ph), Ac is acetyl(CH₃—(C═O)), tBOC is tert-butyloxycarbonyl (tBuO-(C═O)). EX meansexample.

[0181] Further experimental details of the methods of Examples 119, 132,133, 134, 277, 279, 382 and 522 are set out below.

Example 119 Preparation of3,5-dichloro-4-{2,5-dimethyl-7-[2-(tetrahydro-pyran-4-ylamino)-ethylaminol-pyrazolo[1,5a]pyrimidin-3-yl}-benzoic acid methyl ester Formula I where X is CH,R¹ is CH₃, R² is H, A is CH₂, B is CH₂, R³ is CH₃, R⁴ is2,6-dichloro-4-methoxycarbonylphenyl, R⁵ is tetrahydropyranyl

[0182]

[0183] A.4-(7-{2-[tert-Butoxycarbonyl-(tetrahydro-pyran-4-yl)-amino]-ethylamino}-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-3-yl)-3,5-dichloro-benzoicacid methyl ester

[0184] A suspension of methanesulfonic acid4-(7-{2-[tert-butoxycarbonyl-(tetrahydro-pyran-4-yl)-amino]-ethylamino}-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-3-yl)-3,5-dichloro-phenylester (188 mg, 0.276 nunol) from Example 134, step B,1,3-bis(diphenylphosphino)propane (30 mg 0.073 mmol), triethylamine(0.10 mL), and palladium (II) acetate (25 mg, 0.11 mmol) in methanol(3.5 mL)/dimethylsulfoxide (3.5 mL) was degassed with a stream of carbonmonoxide and then shaken for 4 hours at 70° C. under 40 psi carbonmonoxide. The mixture was filtered through Celite, diluted with ethylacetate and washed with water, dried (Na₂SO₄), concentrated underreduced pressure, and chromatographed (3:1 to 1:1 hexanes/ethyl acetate)to afford the product (144 mg, 88%): +APcI MS (M+1)⁺592; ¹H NMR (CDCl₃)δ: 8.04 (s, 2H), 5.83 (br s, 1H), 3.92 (s, 3H), 2.43 (s, 3H), 2.24 (s,3H), 1.53 (s, 9H).

[0185] B.3,5-Dichloro-4-{2,5-dimethyl-7-[2-(tetrahydro-pyran-4-ylamino)-ethylamino]-pyrazolo[1,5-a]pyrimidin-3-yl}-benzoicacid methyl ester

[0186] To {2-[3-(2,6-Dichloro-4-cyano-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-ylamino]-ethyl}-(tetrahydro-pyran-4-yl)-carbamicacid tert-butyl ester (74 mg, 0.12 mmol) was added 2:1ethanol/concentrated aqueous hydrochloric acid (1 mL). The reaction wasstirred 3 hours at room temperature, concentrated under reducedpressure, and then concentrated 3 additional times from ethanol to givea solid that was extracted from saturated sodium bicarbonate withmethylene chloride, the combined extracts were dried (CDCl₃) andconcentrated under reduced pressure to give the title compound (47 mg,80%): +APcI MS (M+1)⁺492; ¹H NMR (methanol-d₄) δ: 8.04 (s, 2H), 5.82 (s,1H), 3.93 (s, 3H), 2.43 (s, 3H), 2.27 (s, 3H).

Example 132 Preparation of3,5-dichloro-4-{2,5-dimethyl-7-[2-(tetrahydro-pyran-4-ylamino)-ethylamino]-pyrazolo[1,5-a]pyrimidin-3-yl}-benzonitrilehydrochloride salt Formula I where X is CH, R¹ is CH₃, R² is H, A isCH₂, B is CH₂, R³ is CH₃, R⁴ is 2,6-dichloro-4-cyanophenyl, R⁵ istetrahydropyranyl

[0187]

[0188] A.{2-{2-[3-(2,6-Dichloro-4-cyano-phenyl)-2,5-dimethyl-pyraolo[1,5-a]pyrimidin-7-ylamino]-ethyl}-(tetrahydro-pyran-4-yl)-carbamic acidtert-butyl ester

[0189] A suspension of methanesulfonic acid4-(7-{2-[tert-butoxycarbonyl-(tetrahydro-pyran-4-yl)-amino]-ethylamino}-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-3-yl)-3,5-dichlorophenylester (10 mg, 0.015 nmmol) from Example 134, step B, zinc cyanide (2.7mg 0.023 mmol), and palladium tetrakistriphenylphosphine (1.5 mg, 0.0013mmol) in dimethylformamide (0.35 mL) was degassed with a stream ofnitrogen and then stirred for 2 hours at 90° C. The mixture wasextracted from saturated aqueous sodium bicarbonate with ethyl acetate,the combined extracts were washed with water, dried (Na₂SO₄),concentrated under reduced pressure, and chromatographed (9:1 to 5:3 to0:1 hexanes/ethyl acetate) to afford the product (10 mg, quantitative):+APcI MS (M+1)⁺ 559; ¹H NMR (CDCl₃) δ: 7.68 (s, 2H), 5.85 (br s, 1H),2.44 (s, 3H), 2.25 (s, 3H), 1.53 (s, 9H).

[0190] B.3,5-Dichloro-4-{2,5-dimethyl-7-[2-(tetrahydro-pyran-4-ylamino)-ethylamino]-pyrazolo[1,5-a]pyrimidin-3-yl}-benzonitrilehydrochloride salt

[0191] To{2-[3-(2,6-Dichloro-4-cyano-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-ylamino]-ethyl}-(tetrahydro-pyran-4-yl)-carbamicacid tert-butyl ester (10 mg, 0.015 mmol) was added 2:1ethanol/concentrated aqueous hydrochloric acid (1 mL). The reaction wasstirred 3 hours at room temperature, concentrated under reducedpressure, and then concentrated 3 additional times from ethanol to givea solid that was triturated from ether to afford the title compound (10mg, quantitative): +APcI MS (M+1)⁺459; ¹H NMR (methanol-d₄) δ: 8.06 (s,2H), 6.90 (s, 1H), 2.62 (s, 3H), 2.32 (s, 3H).

Example 133 Preparation ofN-13-(2,6-dichloro-4-ethyl-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N′-(tetrahydro-pyran-4yl)-ethane-1,2-diaminehydrochloride salt Formula I where X is CH, R¹ is CH₃, R² is H, A isCH₂, B is CH₂, R³ is CH₃, R⁴is 2,6-dichloro-4-ethylphenyl, R⁵ istetrahydropyranyl

[0192]

[0193] A.{2-[3-(2,6-Dichloro-4-ethyl-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-ylamino]-ethyl}-(tetrahydro-pyran-4-yl)-carbamicacid tert-butyl ester

[0194] To a suspension of methanesulfonic acid4-(7-{2-[tert-butoxycarbonyl-(tetrahydro-pyran-4-yl)-amino]-ethylamino}-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-3-yl)-3,5-dichlorophenylester (1.0 g, 1.5 mmol) from Example 134, step B, powdered K₃PO₄ (39 mg0.18 mmol), and dichloro[bis(diphenylphosphino)ferrocene]palladium (60mg, 0.085 mmol) in tetrahydrofuran (7.5 mL) was added triethylborane (1M in THF, 2.9 mL, 2.9 mmol). The mixture was degassed with a stream ofnitrogen and then stirred for 2.5 hours at 75° C. The mixture wasconcentrated under reduced pressure, extracted from saturated aqueoussodium bicarbonate with methylene chloride, dried (Na₂SO₄), andconcentrated under reduced pressure to give crude product (1.07 g).Analysis by MS and ¹H NMR spectroscopy indicated a 1:1 mixture ofproduct and starting material. A portion of the crude material (408 mg)was then resubjected to the above reaction conditions for 2.5 hours,then worked up as before. Chromatography (2:1 hexanes/ethyl acetate)afforded product (176 mg, 56%): +APcI MS (M+1)⁺562; ¹H NMR (methanol-d4)δ: 7.33 (s, 2H), 6.04 (br s, 1H), 2.66 (q, 2H), 2.37 (s, 3H), 2.20 (s,3H), 1.42 (s, 9H), 1.25 (t, 3H).

[0195] B.N-[3-(2,6-Dichloro-4-ethyl-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N′-(tetrahydro-pyran-4-yl)-ethane-1,2-diaminehydrochloride salt

[0196] To{2-[3-(2,6-dichloro-4-ethyl-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-ylamino]-ethyl}-(tetrahydro-pyran-4-yl)-carbamicacid tert-butyl ester (0.18 g, 0.31 mmol) 2:1 ethanol/concentratedaqueous hydrochloric acid (3 mL). The reaction was stirred 15 minutes at50° C., concentrated under reduced pressure, and then concentrated 3additional times from ethanol to give a solid that was triturated fromether to afford the title compound (0.15 g, quantitative): +APcI MS(M+1)⁺462; ¹H NMR (methanol-d4) δ: 7.48 (s, 2H), 6.81 (s, 1H), 2.72 (q,2H), 2.60 (s, 3H), 2.30 (s, 3H), 1.28 (t, 3H).

Example 134 Preparation ofN-[3-(2,6-Dichloro-4-ethynyl-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N′-(tetrahydro-pyran-4-yl)-ethane-1,2-diamineFormula I where X is CH, R¹ is CH₃, R² is H, A is CH₂, B is CH₂, R³ isCH₃, R⁴ is 2,6-dichloro-4-ethynylphenyl, R⁵ is tetrahydropyranyl

[0197]

[0198] A. {2-[3-(2,6-Dichloro-4-hydroxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-ylamino]-ethyl}-(tetrahydro-pyran-4-yl)-carbamic acidtert-butyl ester

[0199] A stirred suspension of the crude3,5-Dichloro-4-{2,5-dimethyl-7-[2-(tetrahydro-pyran-4-ylamino)-ethylamino]-pyrazolo[1,5-a]pyrimidin-3-yl}-phenolhydrobromide salt (8.7 mmol) from Example 382, step A in methylenechloride (100 mL) was adjusted to pH 9.5 with triethyl amine,di-tert-butyl-dicarbonate (3.0 g, 14 mmol) was added and the mixture wasstirred for 2 days. The reaction then extracted from saturated aqueoussodium bicarbonate with methylene chloride, the combined organic layerswere dried (Na₂SO₄) and then concentrated under reduced pressure to givethe carbamate in which the phenol had been partially acylated. To astirred solution of the residue in methanol (50 mL) was added 0.5 Msodium methoxide in methanol (30 mL, 15 mmol). After 1 hour the reactionwas concentrated and then extracted from pH 7 buffer with methylenechloride. The combined extracts were dried (Na₂SO₄), concentrated underreduced pressure and then chromatographed (10:1 ethyl acetate/methanol)to give the product (2.8 g, 58%) as a beige foam: +APcI MS (M+1)⁺ 550;¹H NMR (CDCl₃) δ: 6.70 (s, 2H), 5.84 (s, 1H), 2.51 (s, 3H), 2.24 (s,3H), 1.54 (s, 9H).

[0200] B. Methanesulfonic acid4-(7-{2-[tert-butoxycarbonyl-(tetrahydro-pyran-4-yl)-amino]-ethylamino}-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-3-yl)-3,5-dichloro-phenylester

[0201] To a 0° C. stirred solution of{2-[3-(2,6-Dichloro-4-hydroxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-ylamino]-ethyl}-(tetrahydro-pyran-4-yl)-carbamicacid tert-butyl ester (2.0 g, 3.6 mmol) and 2,6-lutidine (1.2 mL, 11mmol) in methylene chloride was added trifluoromethanesulfonicanhydride, dropwise. After 15 minutes the reaction was extracted fromsaturated aqueous sodium bicarbonate with methylene chloride, thecombined organic layers were dried (Na₂SO₄), concentrated under reducedpressure, concentrated again from toluene to remove the lutidine, andthen chromatographed (2:1 to 3:1 ethyl acetate/hexanes) to give theproduct (1.7 g, 69%) as an off-white foam: +APcI MS (M+1)⁺ 682; ¹H NMR(CDCl₃) δ: 7.37 (s, 2H), 5.84 (s, 1H), 2.45 (s, 3H), 2.25 (s, 3H), 1.53(s, 9H).

[0202] C.{2-[3-(2,6-Dichloro-4-trimethylsilanylethynyl-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-ylamino]-ethyl}-(tetrahydro-pyran-4-yl)-carbamicacid tert-butyl ester

[0203] A suspension of methanesulfonic acid4-(7-{2-[tert-butoxycarbonyl-(tetrahydro-pyran-4-yl)-amino]-ethylamino}-2,5-dimethyl-pyrazolo[1,5 -a]pyrimidin-3-yl)-3,5 -dichlorophenyl ester (1.5g, 2.2 mmol) in acetonitrile (5 mL)/triethylamine (1.9 mL) was degassed(3×) by alternately pulling a vacuum followed by repressurization withnitrogen. Trimethylsilylacetylene (0.50 mL, 3.6 mmol),dichlorobis(triphenylphosphine)palladium (65 mg, 0.093 mmol), andcopper(I) iodide (42 mg, 0.22 mmol) were added, and the mixture wasdegassed (3X) again. The mixture was stirred for 4 hours at 65° C., theblack mixture was extracted from saturated aqueous sodium bicarbonatewith methylene chloride, dried (Na₂SO₄), filtered through Celite,concentrated under reduced pressure, and then chromatographed (7:3hexanes/ethyl acetate) to give the product as a light brown foam (1.2 g,89%): +APcI MS (M+1)⁺630; ¹H NMR (CDCl₃) δ: 7.51 (s, 2H), 5.82 (s, 1H),2.44 (s, 3H), 2.23 (s, 3H), 1.53 (s, 9H), 0.24 (s, 9H).

[0204] D.N-[3-(2,6-Dichloro-4-ethynyl-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N′-(tetrahydro-pyran-4-yl)-ethane-1,2-diamine

[0205] To a stirred solution of{2-[3-(2,6-dichloro-4-trimethylsilanylethynyl-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-ylamino]-ethyl}-(tetrahydro-pyran-4-yl)-carbamicacid tert-butyl ester (1.2 g, 2.0 mmol) in ethanol (2 mL) was added KOH(0.2 g, 8 mmol). After 1 hour, the reaction was cooled to 0° C. and 1:1ethanol/concentrated aqueous hydrochloric acid (4 mL) was added and themixture was allowed to warm to room temperature. After 1 day, thereaction was concentrated under reduced pressure, extracted fromsaturated aqueous sodium bicarbonate with methylene chloride, thecombined extracts were dried (Na₂SO₄), concentrated under reducedpressure, and then chromatographed (4:1 to 10:3 to 3:2 ethylacetate/methanol) to afford the title compound (0.70 g, 78%) as anoff-white solid: +APcI MS (M+1)⁺ 458; ¹H NMR (methanol-d₄) δ: 7.58 (d,1H), 6.10 (s, 1H), 3.76 (s, 1H), 2.39 (s, 3H), 2.23 (s, 3H).

Example 2774-{2-[3-(2,6-Dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-ylamino]-ethylamino}-cyclohexanol

[0206]

[0207] A. Preparation of [2-(4-hydroxy-cyclohexylamino)-ethyl]-carbamicacid tert-butyl ester: A mixture of N-tert-butoxycarbonylglycinal (5 g,31.4 nunol), trans 4-amino-cyclohexanol (3.6 g, 31.4 minol), sodiumcyanoborohydride (1.98 g, 314 mmol) in 1:20 HOAc/MeOH (105 mL) wasstirred at room temperature for 72 h. The reaction mixture was dilutedwith EtOAc and was washed with sat'd aq NaHCO₃, sat aq NaCl, dried, andconcentrated in vacuo to give 3.7 g of an oily residue. MS 259 (MH⁺).

[0208] B. Preparation of 4-(2-amino-ethylamino)-cyclohexanol: Theproduct obtained in step A was treated with 1:1 conc HCl/MeOH (40 mL)and was stirred for 1 hr. The reaction mixture was concentrated in vacuoto give 3.3 g of the desired product. MS 159 (MH⁺).

[0209] C. A solution of7-chloro-3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine(5.1 g, 14.3 numol), triethylamine (15 mL) and the product from step B(3.3 g, 14.3 mmol) was heated under reflux for 17 h. The reactionmixture was cooled to room temperature and the solvent was removed undervacuum. The residue was dissolved in EtOAc, washed with sat'd aq NaHCO₃,sat'd aq NaCl, dried and concentrated. The crude residue was purified onSiO₂-gel using a gradient of 100% EtOAc to 10% Et₂NH/EtOAc to give 400mg of the desired product. A portion of the product (20 mg) was treatedwith 4 M HCl (1 mL) in dioxane (5 ml) and the reaction mixture wasconcentrated in vacuo to give the HCl salt. ¹H NMR (Unity-400, CD₃OD): δ7.2 (s), 6.8 (s), 4.08 (m), 3.65 (s), 3.4 (m), 2.6 (s), 2.3 (s), 2.2(d), 2.05 (d), 1.6-1.3 (m). MS 478 (MH⁺), 480 (MH⁺²).

Example 279 Preparation ofN-[3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N′-(tetrahydro-pyran-4-yl)-ethane-1,2-diaminehydrochloride salt Formula I where X is CH, R¹ is CH₃, R² is H, A isCH₂, B is CH₂, R³ is CH₃, R⁴ is 2,6-dichloro-4-methoxyphenyl, R⁵ istetrahydropyranyl

[0210]

[0211] A. (2,6-Dichloro-4-methoxy-phenyl)-acetonitrile and(2,4-Dichloro-6-methoxy-phenyl)-acetonitrile

[0212] A solution of 1,3-dichloro-2-chloromethyl-5-methoxy-benzene (5.0g, 22 mmol), contaminated with the corresponding 4-chloromethyl anddi-(chloromethyl) isomers (J. Med. Chem., 31, 72 (1988)) in refluxingdichloromethane (30 mL) was treated with tetraethylammonium cyanide infour portions over 25 minutes. Ten minutes after the final addition thereaction was cooled and then extracted from saturated aqueous sodiumbicarbonate with ethyl acetate. The combined organic layers were dried(Na₂SO₄), concentrated under reduced pressure, and then chromatographed(6:1 hexanes/ethyl acetate) to give the title compounds (2:1 ratio, 3.4g, 71%) as a colorless solid.(2,6-Dichloro-4-methoxy-phenyl)-acetonitrile: ¹H NMR (CDCl₃) δ: 6.91 (s,2H), 3.91 (s, 2H), 3.79 (s, 3H).(2,4-Dichloro-6-methoxy-phenyl)-acetonitrile: ¹H NMR (CDCl₃) δ: 7.06 (d,1H), 6.82 (d, 1H), 3.89 (s, 2H), 3.79 (s, 3H).

[0213] B.4-(2,6-Dichloro-4-methoxy-phenyl)-5-methyl-2H-pyrazol-3-ylamine

[0214] To a stirred solution of the(2,6-dichloro-4-methoxy-phenyl)-acetonitrile and(2,4-dichloro-6-methoxy-phenyl)-acetonitrile (20 g, 96 mmol) in ethylacetate (95 mL) was added sodium ethoxide in ethanol (21 wt. %, 95 mL,0.25 mol). The reaction was heated at reflux for 4 hours, and thencooled, diluted with water and washed with diethyl ether. The aqueouslayer was acidified to pH 4 with 1 M HCl and then extracted withmethylene chloride. The combined organic layers were dried (Na₂SO₄) andconcentrated under reduced pressure to give a brown oil (20 g, 83%). Toa solution of the brown oil in benzene (150 mL) was added acetic acid(16 mL), which caused the formation of a colorless precipitate.Hydrazine hydrate was added (7.6 mL, 0.16 mol) and the reaction washeated to reflux, at which point the reaction became homogeneous. After16 hours, an additional portion of hydrazine hydrate was added (5 mL,0.10 mmol) and the mixture was heated for 24 more hours. The reactionwas cooled and then extracted with 1 M HCl. The combined aqueous layerswere adjusted to pH 8 with aqueous ammonium hydroxide (cooled in an icebath) and then extracted with methylene chloride. The combined organiclayers were dried (Na₂SO₄), concentrated under reduced pressure, andthen chromatographed (10:1:0.1 ethyl acetate/diethylamine/methanol) togive the title compound (6 g, 29% from A) as a colorless solid: ¹H NMR(CDCl₃) δ: 6.98 (s, 2H), 3.81 (s, 3H), 2.16 (s, 3H).

[0215] C.3-(2,6-Dichloro-4-methoxy-phenyl)-2-methyl-4H-pyrazolo[1,5-a]pyrimidin-7-one

[0216] To a solution of4-(2,6-dichloro-4-methoxy-phenyl)-5-methyl-2H-pyrazol-3-ylamine (10.1 g,39 mmol) in acetic acid (17 mL) was added methyl acetoacetate. After themixture was heated at reflux for 3 hours it was cooled and then dilutedwith diethyl ether (50 mL) to generate a colorless precipitate. Thesolid was collected by vacuum filtration and washed with additionalether to afford the title compound as a colorless solid (10.3 g, 77%):+APcI MS (M+1)⁺ 338; ¹H NMR (methanol-d4) δ: 7.14 (s, 2H), 5.68 (s, 1H),3.86 (s, 3H), 2.30 (s, 3H), 2.16 (s, 3H).

[0217] D.7-Chloro-3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine

[0218] A suspension of3-(2,6-dichloro-4-methoxy-phenyl)-2-methyl-4H-pyrazolo[1,5-a]pyrimidin-7-one(10.3 g, 31 mmol) in phosphorus oxychloride (60 mL) was stirred atreflux. After 2 hours the homogeneous red solution was concentratedunder reduced pressure and then extracted from saturated sodiumbicarbonate with chloroform. The combined organic layers were dried(Na₂SO₄) and then concentrated under reduced pressure to give the titlecompound (10.2 g, 94%) as a red solid: +APcI MS (M+1)⁺ 356; ¹H NMR(CDCl₃) δ: 7.05 (s, 2H), 6.84 (s, 1H), 3.886 (s, 3H), 2.59 (s, 3H), 2.42(s, 3H).

[0219] EN-[3-(2,6-Dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-ethane-1,2-diamine

[0220] To a stirred solution of ethylene diamine (19 mL, 0.28 mol) inethanol (40 mL) was added a solution of7-chloro-3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine(9.9 g, 28 mmol) in methylene chloride (30 mL), dropwise over 1 hour.After refluxing 2 hours the reaction was concentrated under reducedpressure, extracted from saturated aqueous sodium bicarbonate withchloroform, the combined extracts were dried (Na₂SO₄) and thenconcentrated under reduced pressure to give the title compound as ayellow solid (10.42 g, 98%): +APcI MS (M+1)⁺ 380; ¹H NMR (CDCl₃) δ: 6.97(s, 2H), 5.81 (s, 1H), 3.80 (s, 3H), 3.45 (m, 2H), 3.07 (t, 2H), 2.44(s, 3H), 2.26 (s, 3H).

[0221] FN-[3-(2,6-Dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N′-(tetrahydro-pyran-4-yl)-ethane-1,2-diaminehydrochloride salt

[0222] To a stirred solution ofN-[3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-ethane-1,2-diamine(3.32 g, 8.7 mmol) and tetrahydro-4H-pyran-4-one (1.8 g, 18 mmol) inmethanol (60 mL)/acetic acid (1.6 g) was added sodium cyanoborohydride(1.1 g, 17 mmol), portionwise. After stirring 1 hour the reaction wasconcentrated under reduced pressure and then extracted from saturatedaqueous sodium bicarbonate with ethyl acetate. The combined extractswere dried (Na₂SO₄), concentrated under reduced pressure to give thecrude product as a colorless foam (4.1 g, quant). A solution of theproduct in ether (150 mL) was treated with 1 M ethereal HCl whichgenerated a precipitate that was collected by vacuum filtration to givethe title compound (4.1 g, 94%) as a pink solid: +APcI MS (M+1)⁺ 464; ¹HNMR (methanol-d₄) δ: 7.14 (s, 2H), 6.38 (s, 1H), 4.03 (dd, 2H), 3.94 (brt, 2H), 3.86 (s, 3H), 3.50-3.38 (m, 5H), 2.51 (s, 3H), 2.26 (s, 3H),2.05 (m, 2H), 1.68 (qd, 2H).

Example 382 Preparation ofN-[3-(2,6-dichloro-4-propoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N′-(tetrahydro-pyran-4-yl)-ethane-1,2-diaminehydrochloride salt Formula I where X is CH, R¹ is CH₃, R² is H, A isCH₂, B is CH₂, R³ is CH₃, R⁴ is 2,6-dichloro-4-propoxyphenyl, R⁵ istetrahydropyranyl

[0223]

[0224] A.3,5-Dichloro-4-{2,5-dimethyl-7-[2-(tetrahydro-pyran-4-ylamino)-ethylamino]-pyrazolo[1,5-a]pyrimidin-3-yl}-phenolhydrobromide salt

[0225] A suspension ofN-[3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N′-(tetrahydro-pyran-4-yl)-ethane-1,2-diamine(4.1 g, 8.2 mmol), from Example 279, step F, in concentrated aqueous HBr(30 mL) was stirred at reflux. After 5 hours the reaction wasconcentrated under reduced pressure at 70° C. to give the hydrogenbromide salt as a brown oil (7.35 g). A small portion was trituratedfrom ether to give the product as a brown solid: +APcI MS (M+1)⁺ 450; ¹HNMR (methanol-d₄) δ: 7.00 (s, 2H), 6.85 (s, 1H), 4.11 (t, 2H), 4.02 (dd,2H), 3.60-3.40 (m, 5H), 2.61 (s, 3H), 2.29 (s, 3H), 2.095 (m, 2H), 1.74(qd, 2H).

[0226] B.N-[3-(2,6-Dichloro-4-propoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N′-(tetrahydro-pyran-4-yl)-ethane-1,2-diaminehydrochloride salt

[0227] A solution of crude3,5-Dichloro-4-{2,5-dimethyl-7-[2-(tetrahydro-pyran-4-ylamino)-ethylamino]-pyrazolo[1,5-a]pyrimidin-3-yl}-phenolhydrobromide salt (8.7 mmol) from step A in isopropyl alcohol (50 mL)was adjusted to pH 12 with 6 M aqueous NaOH. Propyl iodide (1.3 mL, 14mmol) was added and the reaction was heated at reflux for 4 hours. Thereaction was cooled and then extracted from saturated aqueous sodiumbicarbonate with methylene chloride, dried (Na₂SO₄), concentrated underreduced pressure, and then chromatographed (10:1:0.1 methylenechloride/methanol/ammonium hydroxide) to give the product (2.0 g, 47%).A solution of the product in ethanol was treated with 1 M ethereal HCl(1 eq., 4.1 mmol), the mixture was concentrated to give a solid whichwas repulped from 1:1 ethanol/ether. The solids were collected to givethe title compound (700 mg) as a colorless solid. The mother liquor wasconcentrated and then repulped from ether to give the remainder of theproduct as an off-white solid (1.3 g): +APcI MS (M+1)⁺ 492; ¹H NMR(methanol-d4) δ: 7.21 (s, 2H), 6.67 (s, 1H), 2.61 (s, 3H), 2.33 (s, 3H),1.10 (t, 3H).

Example 522[3-(2,6-Dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-(6-methyl-piperidin-2-ylmethyl)-amine

[0228]

[0229] A. Preparation of methanesulfonic acid 6-methyl-pyridin-2-ylester: Methanesulfonyl chloride (0.94 mL, 12.18 mimol) was added to asolution of 6-methyl-2-pyridinemethanol (1g, 8.12 mmol) andtriethylamine (1.7 mL, 12.18 mmol) in THF (20 mL) at 0° C. The reactionmixture was stirred for 40 min, then was quenched with sat'd aq NaHCO₃and extracted with EtOAc. The combined organic extracts were washed withsat'd aq NaCl, dried and concentrated in vacuo. The crude residue waschromatographed on SiO₂-gel using 50% EtOAc/hexane to give the productas an oil. ¹H NMR (Unity-400, CDCl₃): δ 7.6 (t), 7.26 (d), 7.15 (d),5.28 (s), 3.1 (s), 2.5 (s).

[0230] B. Preparation of 2-azidomethyl-6-methyl-pyridine: A mixture ofthe mesylate (1.0 g, 9.45 mmol) and sodium azide (610 mg, 9.45 mmol) inDM80 (40 mL) was stirred for 1 hr at room temperature. The reactionmixture was poured into EtOAc and was washed with sat'd aq NaCl, driedand concentrated in vacuo. The crude residue was purified using silicagel chromatography (25% EtOAc/hexanes) to give 936 mg of desiredproduct. ¹H NMR (Unity-400, CDCl₃): δ 7.6 (t), 7.1 (d), 7.08 (d), 4.43(s), 2.54 (s).

[0231] C. Preparation of (6-methyl-piperidin-2-yl)-methylamine: Amixture of the product obtained in Step B (860 mg) and PtO₂ (86 mg) inacetic acid (20 mL) was hydrogenated in a Paar Shaker at 40 psi for 17h. The reaction mixture was filtered and the filtrate was concentratedunder vacuum to give 2 g of the desired product. ¹H NMR (Unity-400,CD₃OD): δ 3.1, 1.93 (s), 1.88 (m), 1.55 (m), 1.28 (dd, 3 H).

[0232] D. Preparation of[3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-(6-methyl-piperidin-2-ylmethyl)-amine):A solution of7-chloro-3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine(50 mg, 0.11 mmol), triethylamine (1 mL) and the product from step C (42mg, 0.22 mmol) in EtOH (3 mL) was heated under reflux for 17 h. Thereaction was concentrated under vacuum. The residue was diluted withsat'd aq NaHCO₃ and the aqueous solution was extracted with EtOAc (3×),dried and concentrated in vacuo. The crude residue was purified on aprep TLC plate using 1.5% Et₂NH/EtOAc to give 36 mg of the desiredproduct. ¹H NMR (Unity-400, CDCl₃): δ 7.0 (s, 2H), 5.94 (s, 1H), 3.8 (s,3H), 3.53 (m), 3.05 (m), 2.8 (m), 2.44 (s, 3H), 2.27 (s, 3H). 1.9 (m),1.7 (m). MS 448 (M). Table of Additional Examples

Ex X R¹ R² R³ R⁴ A-B-N[R⁶]-R⁵ MW 9. N Me H Me 2-Br-4,5-diOMe—Ph(CH2)2—NH—(CH2)2-(3-OMe-4-EtO—Ph) 599.53 10. CH Me H Me 2-Br-6-Cl—Ph(CH2)2—NH-(tetrahydropyran-4-yl) 478.8 11. CH Me H Me 2-Cl—Ph(CH2)2—NH—(CH2)2-(4-OMe—Ph) 486.44 12. CH Me H Me 2-OMe-4-OEt-6-F—Ph(CH2)2—NH-(tetrahydropyran-4-yl) 457.54 13. CH Me H Me2,4-diCl-6-(OSO2CF3)—Ph (CH2)2—NH-(tetrahydropyran-4-yl) 528.43 14. CHMe H Me 2,4-diCl-6-OEt—Ph (CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl)555.5 15. CH Me H Me 2,4-diCl-6-OEt—Ph (CH2)2—NH-(4-ethyleneketal-cHex)534.48 16. CH Me H Me 2,4-diCl-6-OEt—Ph (CH2)2—NH-(tetrahydropyran-4-yl)478.4 17. CH Me H Me 2,4-diCl-6-OEt—Ph (CH2)2—NH-(tetrahydropyran-4-yl)478.41 18. CH Me H Me 2,4-diCl-6-OH—Ph (CH2)2—NH-(tetrahydropyran-4-yl)450.4 19. CH Me H Me 2,4-diCl-6-OMe—Ph (CH2)2—NH-(1-Bn-piperidin-4-yl)553.5 20. CH Me H Me 2,4-diCl-6-OMe—Ph (CH2)2—NH-(4-ethoxyimino-cHex)519.5 21. CH Me H Me 2,4-diCl-6-OMe—Ph (CH2)2—NH-(4-ethyleneketal-cHex)520.5 22. CH Me H Me 2,4-diCl-6-OMe—Ph (CH2)2—NH-(4-isobutoxyimino-cHex)547.5 23. CH Me H Me 2,4-diCl-6-OMe—Ph (CH2)2—NH-(4-methoxyimino-cHex)505.5 24. CH Me H Me 2,4-diCl-6-OMe—Ph (CH2)2—NH-(4-OH-cHex) 478.43 25.CH Me H Me 2,4-diCl-6-OMe—Ph (CH2)2—NH-(7-methoxyimino-azepan-3-yl)520.5 26. CH Me H Me 2,4-diCl-6-OMe—Ph (CH2)2—NH—(CH2)2—OH 424.33 27. CHMe H Me 2,4-diCl-6-OMe—Ph (CH2)2—NH-(tetrahydroypyran-4-yl) 464.4 28. CHMe H Me 2,4-diCl-6-OMe—Ph (CH2)2—NH-cyclohexan-4-oxime 491.42 29. CH iPrH Me 2,4-diCl—Ph (CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl) 539.5230. N Me H Me 2,4-diCl—Ph (CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl)512.44 31. CH Me H Me 2,4-diCl—Ph (CH2)2—NH-(1-Bn-piperidin-4-yl) 523.5132. N Me H Me 2,4-diCl—Ph (CH2)2—NH-(1-Bn-piperidin-4-yl) 524.5 33. CHMe H CF₃ 2,4-diCl—Ph (CH2)2—NH-(1-Bn-piperidin-4-yl) 577.48 34. CH Me HMe 2,4-diCl—Ph (CH2)2—NH-(2-Cl-cHex) 466.84 35. CH Me H Me 2,4-diCl—Ph(CH2)2—NH-(2-Cl-cPent) 452.82 36. CH Me H Me 2,4-diCl—Ph(CH2)2—NH-(2-Me-cHex) 446.42 37. CH Me H Me 2,4-diCl—Ph(CH2)2—NH-(2-OH-cHex) 448.39 38. CH Me H Me 2,4-diCl—Ph(CH2)2—NH-(2-OMe-cHex) 462.42 39. N Me H Me 2,4-diCl—Ph(CH2)2—NH-(2F-cPent) 436.3 40. CH Me H Me 2,4-diCl—Ph(CH2)2—NH-(3-Me-cyclohex-2-enyl) 444.41 41. CH iPr H Me 2,4-diCl—Ph(CH2)2—NH-(4-CF3-cHex) 528.45 42. N Me H Me 2,4-diCl—Ph(CH2)2—NH-(4-methoximino-cHex) 476.4 43. CH Me H Me 2,4-diCl—Ph(CH2)2—NH-(4,4-diMe-cyclohex-2-enyl) 458.43 44. CH Me H Me 2,4-diCl—Ph(CH2)2—NH—(CH2)2-(2-OMe—Ph) 484.42 45. N Me H Me 2,4-diCl—Ph(CH2)2—NH—(CH2)2-(3-OMe-4-EtO—Ph) 529.47 46. CH Me H Me 2,4-diCl—Ph(CH2)2—NH—(CH2)2-(3-OMe-4-OEt—Ph) 528.47 47. CH Me H Me 2,4-diCl—Ph(CH2)2—NH—(CH2)2-(4-OMe—Ph) 484.42 48. CH iPr H Me 2,4-diCl—Ph(CH2)2—NH-(cis-4-CF3-cHex) 528.45 49. CH iPr H Me 2,4-diCl—Ph(CH2)2—NH-(tetrahydropyran-4-yl) 462.43 50. CH Me H Me 2,4-diCl—Ph(CH2)2—NH-(tetrahydropyran-4-yl) 450.44 51. CH Me H Me 2,4-diCl—Ph(CH2)2—NH-(tetrahydropyran-4-yl) 434.37 52. N Me H Me 2,4-diCl—Ph(CH2)2—NH-2-norbornyl 445.4 53. N Me H Me 2,4-diCl—Ph(CH2)2—NH—CHMe—(CH2)2—NEt2 478.5 54. N Me H Me 2,4-diCl—Ph(CH2)2—NH—CHMe—CH2—NEt2 464.4 55. CH Me H Me 2,4-diCl—Ph(CH2)2—NH-cyclohex-2-enyl 430.38 56. CH Me H Me 2,4-diCl—Ph(CH2)2—NH-piperidin-4-yl 433.38 57. CH Me H Me 2,4-diCl—Ph CMe2—CH2—OH422.36 58. CH Me H Me 2,4-diF—Ph (CH2)2—NH—(CH2)2-(3-OMe-4-OEt—Ph)495.57 59. CH Et H Me 2,4-diMe—Ph(CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl) 484.7 60. CH nPr H Me2,4-diMe—Ph (CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl) 498.7 61. CHEt H Me 2,4-diMe—Ph CH2—CHMe—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl)498.7 62. CH nPr H Me 2,4-diMe—PhCH2—CHMe—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl) 512.7 63. CH Me H Me2,4-diOMe-6-Cl—Ph (CH2)2—NH-(1-(5-Et-pyrimidin-2-yl)-piperidin-4-yl)565.11 64. CH Me H Me 2,4-diOMe-6-Cl—Ph(CH2)2-NH-(1-(pyrimidin-2-yl)-piperidin-4-yl) 537.1 65. CH Me H Me2,4-diOMe-6-Cl—Ph (CH2)2—NH-(1-Ac-piperidin-4-yl) 501.02 66. CH Me H Me2,4-diOMe-6-Cl—Ph (CH2)2—NH-(1-COOEt-piperidin-4-yl) 531.0 67. CH Me HMe 2,4-diOMe-6-Cl—Ph (CH2)2—NH-(1-SO2Me-piperidin-4-yl) 537.08 68. CH MeH Me 2,4-diOMe-6-Cl—Ph (CH2)2—NH-(4-(NH-iBu)-cHex) 529.12 69. CH Me H Me2,4-diOMe-6-F—Ph (CH2)2—NH-(1-Ac-piperidin-4-yl) 484.57 70. CH Me H Me2,4-diOMe-6-F—Ph (CH2)2—NH-(1-Bn-piperidin-4-yl) 532.65 71. CH Me H Me2,4-diOMe-6-F—Ph (CH2)2—NH-(4-ethyleneketal-cHex) 499.58 72. CH Me H Me2,4-diOMe-6-F—Ph (CH2)2—NH-(4-oxo-cHex) 455.23 73. CH Me H Me2,4-diOMe-6Cl—Ph (CH2)2—NH-(1-Bn-piperidin-4-yl) 549.1 74. CH Me H Me2,4-diOMe-6Cl—Ph (CH2)2—NH-(1-tBoc-piperidin-4-yl) 559.1 75. CH Me H Me2,4-diOMe-6Cl—Ph (CH2)2—NH-(4-ethyleneketal-cHex) 516 76. CH Me H Me2,4-diOMe-6Cl—Ph (CH2)2—NH-(4-oxo-cHex) 471.99 77. CH Me H Me2,4-diOMe-6Cl—Ph (CH2)2—NH-(tetrahydropyran-4-yl) 459.98 78. CH Me H Me2,4-diOMe-6Cl—Ph (CH2)2—NH-piperidin-4-yl) 458.99 79. CH Me H Me2,4,6-triCl—Ph (CH2)2—NH-(4-(1-morpholino)-cHex) 533.51 80. CH Me H Me2,4,6-triCl—Ph (CH2)2—NH-(4-ethyleneketal-cHex) 524.9 81. CH Me H Me2,4,6-triCl—Ph (CH2)2—NH-(4-NHMe-cHex) 477.44 82. CH Me H Me2,4,6-triCl—Ph (CH2)2—NH-(tetrahydropyran-4-yl) 468.8 83. CH Me H Me2,4,6-triCl—Ph CH2—CHMe—NH-(4-NHMe-cHex) 491.47 84. CH Me H Me2,4,6-triMe—Ph (CH2)2-3-pyridyl 428.58 85. CH Et H Me 2,4,6-triMe—Ph(CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl) 498.7 86. CH Et H Me2,4,6-triMe—Ph (CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl) 512.7 87.CH nPr H Me 2,4,6-triMe—Ph (CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl)512.7 88. CH Me H Me 2,4,6-triMe—Ph(CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl) 484.7 89. CH Me H Me2,4,6-triMe—Ph (CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl) 484.64 90.CH Et H Me 2,4,6-triMe—Ph (CH2)2—NH-(1-Ac-piperidin-4-yl) 462.6 91. CHMe H Me 2,4,6-triMe—Ph (CH2)2—NH-(1-COOEt-piperidin-4-yl) 478.64 92. CHEt H Me 2,4,6-triMe—Ph (CH2)2—NH-(1,2,3,4-tetrahydro-naphthalen-2-yl)467.7 93. CH Me H Me 2,4,6-triMe—Ph(CH2)2—NH—(CH2)2-(1-Me-pyrrolidin-2-yl) 434.63 94. CH Et H Me2,4,6-triMe—Ph (CH2)2—NH—(CH2)2-(3-OMe-4-EtO—Ph) 515.70 95. CH CH3 H Et2,4,6-triMe—Ph (CH2)2—NH—(CH2)2-(3-OMe-4-EtO—Ph) 515.70 96. CH iPr H Me2,4,6-triMe—Ph (CH2)2—NH—(CH2)2-(3-OMe-4-EtO—Ph) 529.73 97. CH nPr H Me2,4,6-triMe—Ph (CH2)2—NH—(CH2)2-(3-OMe-4-EtO—Ph) 529.73 98. CH Ph H Me2,4,6-triMe—Ph (CH2)2—NH—(CH2)2-(3-OMe-4-EtO—Ph) 563.74 99. CH Me H Me2,4,6-triMe—Ph (CH2)2—NH-(trans-4-COOEt-cHex) 477.64 100. CH Me H Me2,4,6-triMe—Ph (CH2)2—NH-(trans-4-COOH-cHex) 449.59 101. CH Et H Me2,4,6-triMe—Ph (CH2)2—NH—CHMe—Ph 441.6 102. CH Me H CH2—OMe2,4,6-triMe—Ph (CH2)2—NH-cPent 421.59 103. CH Me H Me 2,4,6-triMe—Ph(CH2)2—NH-cyclohex-3-enyl 403.6 104. CH Me H Me 2,4,6-triMe—Ph(CH2)3—NH—CH2-(3,4-diOMe—Ph) 487.64 105. CH Me H Me 2,4,6-triMe—Ph(CH2)3—NH—CH2-(4-OMe—Ph) 457.61 106. CH nPr H Me 2,4,6-triMe—PhCH2—CHMe—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl) 526.73 107. CH Et H Me2,4,6-triMe—Ph CH2—CHMe—NH-(1-Ac-piperidin-4-yl) 476.7 108. CH Et H Me2,4,6-triMe—Ph CH2—CHMe—NH-(1,2,3,4-tetrahydro-naphthalen-2-yl) 481.7109. CH Et H Me 2,4,6-triMe—Ph CH2—CHMe—NH—CHMe—Ph 455.65 110. CH Me HMe 2,4,6-triMe—Ph CHiBu—CH2—NH-(tetrahydropyran-4-yl) 463.7 111. CH Me HMe 2,6-diCl-4-(2-oxo-oxazolidin-3-yl)-Ph(CH2)2—NH-(tetrahydropyran-4-yl) 519.4 112. CH Me H Me2,6-diCl-4-(3,5-dimethyl-isoxazol-4-yl)-Ph(CH2)2—NH-(tetrahydropyran-4-yl) 529.47 113. CH Me H Me2,6-diCl-4-(4,5-dihydro-oxazol-2-yl)-Ph (CH2)2—NH-(tetrahydropyran-4-yl)503.4 114. CH Me H Me 2,6-diCl-4-(4H-[1,2,4]triazol-3-yl)(CH2)2—NH-(tetrahydropyran-4-yl) 502.41 115. CH Me H Me2,6-diCl-4-(C═O)-1′-pyrrolidine)-Ph (CH2)2—NH-(tetrahydropyran-4-yl)531.49 116. CH Me H Me 2,6-diCl-4-(C═O)-N—Et)—Ph(CH2)2—NH-(tetrahydropyran-4-yl) 505.45 117. CH Me H Me2,6-diCl-4-(CH(OH)Me2) (CH2)2—NH-(tetrahydropyran-4-yl) 492.45 118. CHMe H Me 2,6-diCl-4-(CH2OH)—Ph (CH2)2—NH-(tetrahydropyran-4-yl) 464.40119. CH Me H Me 2,6-diCl-4-(CO2Me)—Ph (CH2)2—NH-(tetarhydropyran-4-yl)492.41 120. CH Me H Me 2,6-diCl-4-(COOEt)—Ph(CH2)2—NH-(tetrahydropyran-4-yl) 506.44 121. CH Me H Me2,6-diCl-4-(COOH)—Ph (CH2)2—NH-(tetrahydropyran-4-yl) 478.38 122. CH MeH Me 2,6-diC1-4-(cPent-1-ene)-Ph (CH2)2—NH-(tetrahydropyran-4-yl) 500.48123. CH Me H Me 2,6-diCl-4-(isopropene)-Ph(CH2)2—NH-(tetrahydropyran-4-yl) 474.44 124. CH Me H Me2,6-diCl-4-(O(CH2)2—NMe2)—Ph (CH2)2—NH-(tetrahydropyran-4-yl) 521.5 125.CH Me H Me 2,6-diCl-4-CH2OMe—Ph (CH2)2—NH-(tetrahydropyran-4-yl) 478.4126. CH Me H Me 2,6-diCl-4-CHO—Ph (CH2)2—NH-(tetrahydropyran-4-yl)477.40 127. CH Me H Me 2,6-diCl-4-CN—Ph(CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl) 536.5 128. CH Me H Me2,6-diCl-4-CN—Ph (CH2)2—NH-(1-(SO2—N—(Me)2)-piperidin-4-yl) 565.53 129.CH Me H Me 2,6-diCl-4-Cn—Ph (CH2)2—NH-(1-Bn-piperidin-4-yl) 548.52 130.CH Me H Me 2,6-diCl-4-CN—Ph (CH2)2—NH-(1-propanoyl-piperidin-4-yl)514.46 131. CH Me H Me 2,6-diCl-4-CN—Ph(CH2)2—NH-(1-SO2Me-piperidin-4-yl) 536.5 132. CH Me H Me2,6-diCl-4-CN—Ph (CH2)2—NH-(tetrahydropyran-4-yl) 459.38 133. CH Me H Me2,6-diCl-4-Et—Ph (CH2)2—NH-(tetrahydropyran-4-yl) 462.42 134. CH Me H Me2,6-diCl-4-ethynyl-Ph (CH2)2—NH-(tetrahydropyran-4-yl) 458.4 135. CH MeH Me 2,6-diCl-4-ethynyl-PhCH2—CHMe—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl) 535.5 136. CH Me H Me2,6-diCl-4-OEt—Ph (CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl) 555.22137. N Me H Me 2,6-diCl-4-OEt—Ph(CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl) 556.5 138. CH Me H Me2,6-diCl-4-OEt—Ph (CH2)2—NH-(1-Ac-piperidin-4-yl) 519.5 139. N Me H Me2,6-diCl-4-OEt—Ph (CH2)2—NH-(1-Ac-piperidin-4-yl) 520.5 140. CH Me H Me2,6-diCl-4-OEt—Ph (CH2)2—NH-(1-benzoyl-piperidin-4-yl) 567.6 141. N Me HMe 2,6-diCl-4-OEt—Ph (CH2)2—NH-(1-COOEt-piperidin-4-yl) 550.5 142. CH MeH Me 2,6-diCl-4-OEt—Ph (CH2)2—NH-(1-propanoyl-piperidin-4-yl) 533.5 143.CH Me H Me 2,6-diCl-4-OEt—Ph (CH2)2—NH-(1-SO2Me-piperidin-4-yl) 555.5144. N Me H Me 2,6-diCl-4-OEt—Ph (CH2)2—NH-(1-SO2Me-piperidin-4-yl)556.5 145. CH Me H Me 2,6-diCl-4-OEt—Ph(CH2)2—NH-(1-SO2Me-piperidin-4-yl) 555.52 146. CH Me H Me2,6-diCl-4-OEt—Ph (CH2)2—NH-(1-SO2NMe2-piperidin-4-yl) 584.6 147. N Me HMe 2,6-diCl-4-OEt—Ph (CH2)2—NH-(1-tBoc-piperidin-4-yl) 578.53 148. CH MeH Me 2,6-diCl-4-OEt—Ph (CH2)2—NH-(2-Me-tetrahydro-furan-3-yl) 478.43149. CH Me H Me 2,6-diCl-4-OEt—Ph (CH2)2—NH-(2-OEt-cHex) 520.51 150. CHMe H Me 2,6-diCl-4-OEt—Ph (CH2)2—NH-(2-OH-cHex) 492.45 151. CH Me H Me2,6-diCl-4-OEt—Ph (CH2)2—NH-(2-oxo-pyrrolidin-4-yl) 447.4 152. N Me H Me2,6-diCl-4-OEt—Ph (CH2)2—NH-(2F-cPent) 481.40 153. CH Me H Me2,6-diCl-4-OEt—Ph (CH2)2—NH-(4-COOEt-cHex) 548.52 154. CH Me H Me2,6-diCl-4-OEt—Ph (CH2)2—NH-(4-ethyleneketal-cHex) 534.5 155. N Me H Me2,6-diCl-4-OEt—Ph (CH2)2—NH-(4-ethyleneketal-cHex) 535.47 156. N Me H Me2,6-diCl-4-OEt—Ph (CH2)2—NH-(4-NHSO2Me-cHex) 570.5 157. CH Me H Me2,6-diCl-4-OEt—Ph (CH2)2—NH-(4-OH-cHex) 492.5 158. N Me H Me2,6-diCl-4-OEt—Ph (CH2)2—NH-(4-OH-cHex) 493.43 159. CH Me H Me2,6-diCl-4-OEt—Ph (CH2)2—NH-(4-oxo-cHex) 490.5 160. N Me H Me2,6-diCl-4-OEt—Ph (CH2)2—NH-(4-oxo-cHex) 491.41 161. CH Me H Me2,6-diCl-4-OEt—Ph (CH2)2—NH-(4,4-Me2-lacton-3-yl) 506.4 162. CH Me H Me2,6-diCl-4-OEt—Ph (CH2)2—NH-(6-azabicyclo[4.4.0]dec-3-yl) 531.53 163. CHMe H Me 2,6-diCl-4-OEt—Ph (CH2)2—NH-(7-oxo-azepan-3-yl) 505.45 164. N MeH Me 2,6-diCl-4-OEt—Ph (CH2)2—NH—(CH2)2—OH 439.3 165. N Me H Me2,6-diCl-4-OEt—Ph (CH2)2—NH—(CH2)3—OH 453.4 166. N Me H Me2,6-diCl-4-OEt—Ph (CH2)2—NH—(CH2)3—OMe 467.4 167. N Me H Me2,6-diCl-4-OEt—Ph (CH2)2—NH—(CH2)—(R)—CHMe—OH 453.4 168. N Me H Me2,6-diCl-4-OEt—Ph (CH2)2—NH—(S)—CHMe—CH2—OH 453.4 169. CH Me H Me2,6-diCl-4-OEt—Ph (CH2)2—NH-(tetrahydropyran-4-yl) 478.4 170. CH Et H Me2,6-diCl-4-OEt—Ph (CH2)2—NH-(tetrahydropyran-4-yl) 492.5 171. N Me H Me2,6-diCl-4-OEt—Ph (CH2)2—NH-(tetrahydropyran-4-yl) 479.4 172. N Me H Me2,6-diCl-4-OEt—Ph (CH2)2—NH-(trans-4-COOEt-cHex) 549.49 173. N Me H Me2,6-diCl-4-OEt—Ph (CH2)2—NH-(trans-4-OH-piperidin-4-yl) 493.4 174. CH MeH Me 2,6-diCl-4-OEt—Ph (CH2)2—NH—CH2-(1-tBoc-piperidin-4-yl) 591.59 175.CH Me H Me 2,6-diCl-4-OEt—Ph (CH2)2—NH—CH2-(piperidin-4-yl) 491.47 176.CH Me H Me 2,6-diCl-4-OEt—Ph (CH2)2—NH—CH2—CF3 476.33 177. CH Me H Me2,6-diCl-4-OEt—Ph (CH2)2—NH—CH2—CHOH—CH2OH 468.39 178. CH Me H Me2,6-diCl-4-OEt—Ph (CH2)2—NH—CHMe-(1-Ac-piperidin-4-yl) 547.5 179. CH MeH Me 2,6-diCl-4-OEt—Ph (CH2)2—NH—CHMe-(1-tBoc-piperidin-4-yl) 605.61180. CH Me H Me 2,6-diCl-4-OEt—Ph (CH2)2—NH—CHMe-(piperidin-4-yl) 505.49181. CH Me H Me 2,6-diCl-4-OEt—Ph (CH2)2—NH-cyclohex-3-enyl 475.4 182.CH Me H Me 2,6-diCl-4-OEt—Ph (CH2)2—NH-cyclohex-3-enyl 474.4 183. CH MeH Me 2,6-diCl-4-OEt—Ph (CH2)2—NH-cyclohexan-4-oxime 505.5 184. N Me H Me2,6-diCl-4-OEt—Ph (CH2)2—NH-piperidin-4-yl 480.43 185. CH Me H Me2,6-diCl-4-OEt—Ph CH2—CHMe—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl) 569.54186. CH Me H Me 2,6-diCl-4-OEt—Ph CH2—CHMe—NH-(4-ethyleneketal-cHex)548.52 187. CH Me H Me 2,6-diCl-4-OEt—Ph CH2—CHMe—NH-(4-OH-cHex) 506.48188. CH Me H Me 2,6-diCl-4-OEt—Ph CH2—CHMe—NH-(tetrahydropyran-4-yl)492.45 189. CH Me H Me 2,6-diCl-4-OEt—PhCH2—CMe2—NH-(tetrahydropyran-4-yl) 506.48 190. CH Me H Me2,6-diCl-4-OEt—Ph CHMe—CH2—NH-(tetrahydropyran-4-yl) 492.45 191. CH Me HMe 2,6-diCl-4-OH—Ph (CH2)2—NH-(1-Bn-piperidin-4-yl) 539.51 192. CH Me HMe 2,6-diCl-4-OH—Ph (CH2)2—NH-(1-Ph-pyrrolidin-3-yl) 511.46 193. CH Me HMe 2,6-diCl-4-OH—Ph (CH2)2—NH-(4-ethyleneketal-cHex) 506.44 194. CH Me HMe 2,6-diCl-4-OH—Ph (CH2)2—NH-(4-oxo-cHex) 462.38 195. CH Me H Me2,6-diCl-4-OH—Ph (CH2)2—NH-(6-azabicyclo[4.4.0]dec-3-yl) 503.48 196. CHMe H Me 2,6-diCl-4-OH—Ph (CH2)2—NH-(tetrahydropyran-4-yl) 450.4 197. CHEt H Me 2,6-diCl-4-OH—Ph (CH2)2—NH-(tetrahydropyran-4-yl) 464.4 198. CHMe H Me 2,6-diCl-4-OH—Ph (CH2)2—NH—CHMe—CH2-(3-OMe-4-OEt—Ph) 530.46 199.CH Me H Me 2,6-diCl-4-OH—Ph (CH2)2—NH—CHMe—CH2—NMe2 451.4 200. CH Me HMe 2,6-diGl-4-OH—Ph CH2—CHMe—NH-(4-(1-morpholino)-cHex) 547.53 201. CHMe H Me 2,6-diCl-4-OH—Ph CH2—CHMe—NH-(tetrahydropyran-4-yl) 464.4 202.CH Me H Me 2,6-diCl-4-OH—Ph CHMe—CHMe—NH-(tetrahydropyran-4-yl) 478.43203. CH Me H Me 2,6-diCl-4-OiPr—Ph (CH2)2—NH-(tetrahydropyran-4-yl)492.45 204. CH Me H Me 2,6-diCl-4-OMe—Ph2-(NH-(1-Bn-piperidin-4-yl))-cHex 607.63 205. CH Me H Me2,6-diCl-4-OMe—Ph 2-(NH-(1-Bn-piperidin-4-yl))-cHex 607.63 206. CH Me HMe 2,6-diCl-4-OMe—Ph 2-(NH-(tetrahydropyran-4-yl))-cHex 518.49 207. CHMe H Me 2,6-diCl-4-OMe—Ph 2-(NH-(tetrahydropyran-4-yl))-cHex 518.49 208.CH Me H Me 2,6-diCl-4-OMe—Ph 3-(NH-(1-Bn-piperidin-4-yl))-cHex 607.63209. CH Me H Me 2,6-diCl-4-OMe—Ph 3-(NH-(tetrahydropyran-4-yl))-cHex518.49 210. CH Me H Me 2,6-diCl-4-OMe—Ph4-(NH-(tetrahydropyran-4-yl))-cHex 518.49 211. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—CHEt—NH-(1-Bn-piperidin-4-yl) 595.62 212. CH MeH Me 2,6-diCl-4-OMe—Ph (CH2)2—CHEt—NH-(tetrahydropyran-4-yl) 506.48 213.CH iPr H Me 2,6-diCl-4-OMe—Ph (CH2)2—CHEt—NH-(tetrahydropyran-4-yl)534.5 214. CH Me H Me 2,6-diCl-4-OMe—Ph (CH2)2—N((CH2)3—CF3)2 600.44215. CH Me H Me 2,6-diCl-4-OMe—Ph (CH2)2—N(CH2-2-(CH2OH)-furan-5-yl)2600.51 216. CH Me H Me 2,6-diCl-4-OMe—Ph(CH2)2—N[CH2-2-pyridyl]-(1-(CH2-2-pyridyl)-piperidin-4-yl) 645.64 217.CH Me H Me 2,6-diCl-4-OMe—Ph(CH2)2—N[CH2-3-pyridiyl)]-(1-(CH2-3-pyridyl)-piperidin-4-yl) 645.64 218.CH Me H Me 2,6-diCl-4-OMe—Ph (CH2)2—N(CH2—CHOH—CH2OH)2 528.44 219. CH MeH Me 2,6-diCl-4-OMe—Ph (CH2)2-N-propanoyl-(1-propanoyl-piperidin-4-yl)575.54 220. CH Me H Me 2,6-diCl-4-OMe—Ph(CH2)2-NEt-(tetrahydropyran-4-yl) 492.45 221. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH-(1-(CH2-2-pyridyl)-piperidin-4-yl) 554.53222. CH Me H Me 2,6-diCl-4-OMe—Ph(CH2)2—NH-(1-(CH2-3-pyridyl)-piperidin-4-yl) 554.53 223. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH-(1-(CH2-4-pyridyl)-piperidin-4-yl) 554.53224. CH Me H Me 2,6-diCl-4-OMe—Ph(CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl) 541.5 225. CH Et H Me2,6-diCl-4-OMe—Ph (CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl) 555.52226. CH Me H Me 2,6-diCl-4-OMe—Ph (CH2)2—NH-(1-Ac-piperidin-4-yl) 504.46227. CH Me Me Me 2,6-diCl-4-OMe—Ph (CH2)2—NH-(1-Ac-piperidin-4-yl) 519.5228. CH Me H Me 2,6-diCl-4-OMe—Ph (CH2)2—NH-(1-Bn-piperidin-4-yl) 553.5229. CH Me H Me 2,6-diCl-4-OMe—Ph (CH2)2—NH-(1-Et-piperidin-3-yl) 491.5230. CH Me H Me 2,6-diCl-4-OMe—Ph (CH2)2—NH-(1-Et-piperidin-4-yl) 491.5231. CH Me H Me 2,6-diCl-4-OMe—Ph (CH2)2—NH-(1-iPr-piperidin-4-yl) 505.5232. CH Me H Me 2,6-diCl-4-OMe—Ph (CH2)2—NH-(1-Me-piperidin-4-yl) 477.44233. CH Me H Me 2,6-diCl-4-OMe—Ph (CH2)2—NH-(1-Ph-pyrrolidin-3-yl)525.49 234. CH Me H Me 2,6-diCl-4-OMe—Ph(CH2)2—NH-((1-phenylethyl)-pyrrolidin-2-one-4-yl) 567.52 235. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH-(1-phenylethyl-piperidin-4-yl) 567.57 236.CH Me H Me 2,6-diCl-4-OMe—Ph (CH2)2—NH-(1-propanoyl-piperidin-4-yl)519.5 237. CH Me H Me 2,6-diCl-4-OMe—Ph(CH2)2—NH-(1-SO2Me-piperidin-4-yl) 541.5 238. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH-(1-SO2NMe2-piperidin-4-yl) 570.5 239. CH EtH Me 2,6-diCl-4-OMe—Ph (CH2)2-NH-(1,2,3,4-tetrahydro-naphthalen-2-yl)524.5 240. CH Me H Me 2,6-diCl-4-OMe—Ph (CH2)2—NH-(2-CF3-cHex) 530.4241. CH Me H Me 2,6-diCl-4-OMe—Ph (CH2)2—NH-(2-Me-tetrahydrofuran-3-yl)464.40 242. CH Me H Me 2,6-diCl-4-OMe—Ph(CH2)2—NH-(2-oxo-pyrrolidin-4-yl) 463.37 243. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH-((2,2,6,6-tetramethyl)-piperidin-4-yl) 519.5244. CH Me H Me 2,6-diCl-4-OMe—Ph (CH2)2—NH-(2F-cHex) 480.4 245. CH Me HMe 2,6-diCl-4-OMe—Ph (CH2)2—NH-(4-(1-azetidino)-cHex) 517.51 246. CH MeH Me 2,6-diCl-4-OMe—Ph (CH2)2—NH-(4-(1-morpholino)-cHex) 547.53 247. CHMe H Me 2,6-diCl-4-OMe—Ph (CH2)2—NH-(4-(1-piperidino)-cHex) 545.56 248.CH Me H Me 2,6-diCl-4-OMe—Ph (CH2)2—NH-(4-(1-pyrrolidino)-cHex) 531.53249. CH Me H Me 2,6-diCl-4-OMe—Ph (CH2)2—NH-(4-(NH—CH2-2-pyridyl)-cHex)568.55 250. CH Me H Me 2,6-diCl-4-OMe—Ph(CH2)2—NH-(4-(NH—CH2—CH2—CH2OH)-cHex) 521.49 251. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH-(4-(NH2)-cHex) 477.44 252. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH-(4-(NHAc)-cHex) 519.48 253. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH-(4-(NHSO2Me)-cHex) 555.53 254. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH-(4-CF3-cHex) 530.42 255. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH-(4-CF3-cHex) 530.4 256. CH iPr H Me2,6-diCl-4-OMe—Ph (CH2)2—NH-(4-CF3-cHex) 558.5 257. CH Et H Me2,6-diCl-4-OMe—Ph (CH2)2—NH-(4-CF3-cHex) 544.5 258. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH-(4-ethyleneketal-cHex) 520.5 259. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH-(4-hydroxyimino-cHex) 491.42 260. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH-(4-NHCOOMe-cHex) 535.5 261. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH-(4-NHEt-cHex) 505.50 262. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH-(4-NHiBu-cHex) 533.55 263. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH-(4-NHMe-cHex) 491.47 264. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH-(4-NHpropanoyl-cHex) 533.5 265. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH-(4-OH-cHex) 478.43 266. CH Et H Me2,6-diCl-4-OMe—Ph (CH2)2—NH-(4,4-Dimethyl-2-oxo-tetrahydro-furan-3-yl)506.44 267. CH Me H Me 2,6-diCl-4-OMe—Ph (CH2)2—NH-(5-Cl-indan-1-yl)530.89 268. CH Me H Me 2,6-diCl-4-OMe—Ph(CH2)2—NH-(5-fluorindolin-2-one-3-yl) 529.41 269. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH-(6-azabicyclo[4.4.0]dec-3-yl) 517.51 270. CHMe H Me 2,6-diCl-4-OMe—Ph(CH2)2—NH-(6-OMe-1,2,3,4-tetrahydro-naphthalen-1-yl) 540.5 271. CH Me HMe 2,6-diCl-4-OMe—Ph (CH2)2—NH-(7-methoxyimino-azepan-3-yl 520.47 272.CH Me H Me 2,6-diCl-4-OMe—Ph (CH2)2—NH—(CH2)2—CF3 476.3 273. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH—(CH2)2—OH 424.33 274. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH—(CH2)3—CF3 490.336 275. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH-(cis-2F-cHex) 480.4 276. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH-(cis-4-NHiBu-cHex) 533.55 277. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH-(trans-4-OH-cHex)-#277a 478.43(CH2)2—NH-(cis-4OH-cHex)-#277b 278. CH Me H Me 2,6-diCl-4-OMe—Ph(CH2)2—NH-(furan-2-one-4-yl) 464.36 279. CH Me H Me 2,6-diCl-4-OMe—Ph(CH2)2—NH-(tetrahydropyran-4-yl) 464.4 280. CH Et H Me 2,6-diCl-4-OMe—Ph(CH2)2—NH-(tetrahydropyran-4-yl) 478.4 281. CH tBu H Me2,6-diCl-4-OMe—Ph (CH2)2—NH-(tetrahydropyran-4-yl) 506.5 282. CH nPr HMe 2,6-diCl-4-OMe—Ph (CH2)2—NH-(tetrahydropyran-4-yl) 492.5 283. CH iPrH Me 2,6-diCl-4-OMe—Ph (CH2)2—NH-(tetrahydropyran-4-yl) 492.5 284. CHCF3 H Me 2,6-diCl-4-OMe—Ph (CH2)2—NH-(tetrahydropyran-4-yl) 518.4 285. NMe H Me 2,6-diCl-4-OMe—Ph (CH2)2—NH-(tetrahydropyran-4-yl) 465.38 286.CH Me H Me 2,6-diCl-4-OMe—Ph (CH2)2—NH-(trans-2F-cHex) 480.4 287. CH MeH Me 2,6-diCl-4-OMe—Ph (CH2)2—NH-(trans-4-NHiBu-cHex) 533.55 288. CH MeH Me 2,6-diCl-4-OMe—Ph (CH2)2—NH-(trans-4-OH-piperidin-4-yl) 478.4 289.CH Me H Me 2,6-diCl-4-OMe—Ph (CH2)2—NH-Bn 470.41 290. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH—CH—(CH2OH)2 454.36 291. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH—CH2-(1-tBoc-piperidin-4-yl) 577.56 292. CHMe H Me 2,6-diCl-4-OMe—Ph (CH2)2—NH—CH2-(2-Me-oxetan-2-yl) 464.4 293. CHMe H Me 2,6-diCl-4-OMe—Ph (CH2)2—NH—CH2-(piperidin-4-yl) 477.44 294. CHMe H Me 2,6-diCl-4-OMe—Ph (CH2)2—NH—CH2-2-(CH2OH)-furan-5-yl 490.39 295.CH Et H Me 2,6-diCl-4-OMe—Ph (CH2)2—NH—CH2-2-CF3—Ph 552.43 296. CH Me HMe 2,6-diCl-4-OMe—Ph (CH2)2—NH—CH2-2-pyridyl 471.39 297. CH Et H Me2,6-diCl-4-OMe—Ph (CH2)2—NH—CH2-3-CF3—Ph 552.43 298. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH—CH2-3-pyridyl 471.39 299. CH Et H Me2,6-diCl-4-OMe—Ph (CH2)2—NH—CH2-4-CF3—Ph 552.43 300. CH Et H Me2,6-diCl-4-OMe—Ph (CH2)2—NH—CH2-4-Cl—Ph 518.88 301. CH Et H Me2,6-diCl-4-OMe—Ph (CH2)2—NH—CH2-4-OCF3—Ph 568.43 302. CH Et H Me2,6-diCl-4-OMe—Ph (CH2)2—NH—CH2-4-OMe—Ph 514.46 303. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH—CH2-4-pyridyl 471.39 304. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH—CH2—CF3 462.31 305. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH—CH2—CHOH—CH2OH 454.36 306. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH—CH2—CHOH—Me 438.36 307. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH—CH2CHF2 444.3 308. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH—CH2CHFPh 502.4 309. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH—CHEt—CH2OH 452.39 310. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH—CHet—Ph 498.46 311. CH Et H Me2,6-diCl-4-OMe—Ph (CH2)2—NH—CHEt—Ph 512.49 312. CH nPr H Me2,6-diCl-4-OMe—Ph (CH2)2—NH—CHEt—Ph 526.51 313. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH—CHMe-(1-Et-piperidin-4-yl) 533.51 314. CH MeH Me 2,6-diCl-4-OMe—Ph (CH2)2—NH—CHMe-(1-SO2Me-piperidin-4-yl) 569.6315. CH Me H Me 2,6-diCl-4-OMe—Ph (CH2)2—NH—CHMe-(1-tBoc-piperidin-4-yl)591.59 316. CH Me H Me 2,6-diCl-4-OMe—Ph (CH2)2—NH—CHMe-(CH2)3-NEt2521.54 317. CH Me H Me 2,6-diCl-4-OMe—Ph (CH2)2—NH—CHMe-(piperidin-4-yl)491.47 318. CH Et H Me 2,6-diCl-4-OMe—Ph (CH2)2—NH—CHMe-4-Cl—Ph 532.90319. CH Et H Me 2,6-diCl-4-OMe—Ph (CH2)2—NH—CHMe-4-F—Ph 516.45 320. CHMe H Me 2,6-diCl-4-OMe—Ph (CH2)2—NH—CHMe—CH2—F 440.4 321. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH—CHMe—CH2—NEt2 493.48 322. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH—CHMe—CH2—NMe2 465.43 323. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH—CHMe—Ph 484.43 324. CH Et H Me2,6-diCl-4-OMe—Ph (CH2)2—NH—CHMe—Ph 498.46 325. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH—CHMe-piperidin-4-yl 477.44 326. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH-cyclohex-3-enyl 460.4 327. CH nPr H Me2,6-diCl-4-OMe—Ph (CH2)2—NH-cyclohex-3-enyl 488.5 328. CH Et H Me2,6-diCl-4-OMe—Ph (CH2)2—NH-cyclohex-3-enyl 474.4 329. CH Me Me Me2,6-diCl-4-OMe—Ph (CH2)2—NH-cyclohex-3-enyl 474.4 330. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH-cyclopent-3-enyl 446.38 331. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH-piperidin-4-yl 463.41 332. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NH-tropin-3-yl 488.4 333. CH Me Et Me2,6-diCl-4-OMe—Ph (CH2)2—NHEt 436.39 334. CH Me H Me 2,6-diCl-4-OMe—Ph(CH2)2—NMe-(1-Ac-piperidin-4-yl) 519.5 335. CH Me Me Me2,6-diCl-4-OMe—Ph (CH2)2—NMe-(tetrahydropyran-4-yl) 533.51 336. CH Me HMe 2,6-diCl-4-OMe—Ph (CH2)2—NMe-(tetrahydropyran-4-yl) 478.4 337. CH MeMe Me 2,6-diCl-4-OMe—Ph (CH2)2—NMe-cyclohex-3-enyl 488.5 338. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)2—NMe-cyclohex-3-enyl 474.4 339. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)3—NH-(1-Bn-piperidin-4-yl) 567.57 340. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)3—NH-tetrahydropyran-4-yl 478.43 341. CH Me H Me2,6-diCl-4-OMe—Ph (CH2)4—NH-(tetrahydropyran-4-yl) 492.45 342. CH Me HMe 2,6-diCl-4-OMe—Ph CH2—(S)-pyrrolidin-2-yl 420.34 343. CH Me H Me2,6-diCl-4-OMe—Ph CH2—CH(CH2-imidazol-1-yl)-NH-(1-Bn-piperidin-4-yl)633.63 344. CH Me H Me 2,6-diCl-4-OMe—PhCH2—CH(CH2-imidazol-1-yl)-NH-(tetrahydropyran-4-yl) 544.49 345. CH Me HMe 2,6-diCl-4-OMe—Ph CH2—CHEt—NH-(1-Ac-piperidin-4-yl) 533.5 346. CH MeH Me 2,6-diCl-4-OMe—Ph CH2—CHEt—NH-(tetrahydropyran-4-yl) 492.5 347. CHMe H Me 2,6-diCl-4-OMe—Ph CH2—CHiBu—NH-(tetrahydropyran-4-yl) 520.52348. CH Me H Me 2,6-diCl-4-OMe—Ph CH2—CHiPr—NH-(tetrahydropyran-4-yl)506.5 349. CH iPr H Me 2,6-diCl-4-OMe—PhCH2—CHMe—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl) 583.57 350. CH nPr H Me2,6-diCl-4-OMe—Ph CH2—CHMe—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl) 583.57351. CH Et H Me 2,6-diCl-4-OMe—PhCH2—CHMe—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl) 569.54 352. CH Me H Me2,6-diCl-4-OMe—Ph CH2—CHMe—NH-(4-(1-morpholino)-cHex) 561.56 353. CH MeH Me 2,6-diCl-4-OMe—Ph CH2—CHMe—NH-(4-(1-morpholino)-cHex) 575.59 354.CH Me H Me 2,6-diCl-4-OMe—Ph CH2—CHMe—NH-(4-ethyleneketal-cHex) 534.49355. CH Me H Me 2,6-diCl-4-OMe—Ph CH2—CHMe—NH-(4-NHMe-cHex) 505.50 356.CH Me H Me 2,6-diCl-4-OMe—Ph CH2—CHMe—NH-(4-OH-cHex) 492.45 357. CH Me HMe 2,6-diCl-4-OMe—Ph CH2—CHMe—NH-(4-oxo-cHex) 490.44 358. CH Me H Me2,6-diCl-4-OMe—Ph CH2—CHMe—NH-(tetrahydropyran-4-yl) 478.4 359. CH Et HMe 2,6-diCl-4-OMe—Ph CH2—CHMe—NH-(tetrahydropyran-4-yl) 492.5 360. CHiPr H Me 2,6-diCl-4-OMe—Ph CH2—CHMe—NH-(tetrahydropyran-4-yl) 506.48361. CH nPr H Me 2,6-diCl-4-OMe—Ph CH2—CHMe—NH-(tetrahydropyran-4-yl)506.5 362. CH Me H Me 2,6-diCl-4-OMe—Ph CH2—CHNH2—CH2-imidazol-1-yl460.37 363. CH Me H Me 2,6-diCl-4-OMe—PhCH2—CHOH—CH2—NH-(1-Bn-piperidin-4-yl) 583.57 364. CH Me H Me2,6-diCl-4-OMe—Ph CH2—CHOH—CH2—NH-(tetrahydropyran-4-yl) 494.43 365. CHMe H Me 2,6-diCl-4-OMe—Ph CH2—CHOH—CH2—NH2 410.31 366. CH Me H Me2,6-diCl-4-OMe—Ph CH2—CMe2—CH2—NH-(1-Bn-piperidin-4-yl) 595.62 367. CHMe H Me 2,6-diCl-4-OMe—Ph CH2—CMe2—CH2—NH-(tetrahydropyran-4-yl) 506.48368. CH Me H Me 2,6-diCl-4-OMe—Ph CH2—CMe2—NH-(1-Bn-piperidin-4-yl)581.59 369. CH Me H Me 2,6-diCl-4-OMe—PhCH2—CMe2—NH-(tetrahydropyran-4-yl) 492.45 370. CH Me Me Me2,6-diCl-4-OMe—Ph CH2—NH-(tetrahydropyran-4-yl) 478.4 371. CH Me H Me2,6-diCl-4-OMe—Ph CHEt—CH2—NH-(1-Ac-piperidin-4-yl) 533.5 372. CH Me HMe 2,6-diCl-4-OMe—Ph CHEt—CH2—NH-(tetrahydropyran-4-yl) 492.5 373. CH MeH Me 2,6-diCl-4-OMe—Ph CHiBu—CH2—NH-(tetrahydropyran-4-yl) 520.52 374.CH Me H Me 2,6-diCl-4-OMe—Ph CHMe—CHMe—NH(1-COOEt-piperidin-4-yl) 563.5375. CH Me H Me 2,6-diCl-4-OMe—Ph CHMe—CHMe—NH-(tetrahydropyran-4-yl)492.45 376. CH Me H Me 2,6-diCl-4-OMe—PhCHMe—CHMe—NH-(tetrahydropyran-4-yl) 506.48 377. CH Et H Me2,6-diCl-4-OMe—Ph CHMe—CHMe—NH-(tetrahydropyran-4-yl) 506.5 378. CH Me HMe 2,6-diCl-4-OMe—Ph CMe2—CH2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl)569.5 379. CH Me H Me 2,6-diCl-4-OMe—PhCMe2—CH2—NH-(tetrahydropyran-4-yl) 492.5 380. CH Me H Me2,6-diCl-4-OMe—Ph CMe2—CH2—NH—C(Me)2—CH2—OH 480.4 381. CH Me H Me2,6-diCl-4-OMe—Ph quinuclidin-3-yl 446.38 382. CH Me H Me2,6-diCl-4-OPr—Ph (CH2)2—NH-(tetrahydropyran-4-yl) 492.45 383. CH Me HMe 2,6-diCl-4-OSO2CF3—Ph (CH2)2—NH-(tetrahydropyran-4-yl) 582.43 384. CHEt H Me 2,6-diCl—Ph (CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl) 525.5385. CH iPr H Me 2,6-diCl—Ph(CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl) 539.5 386. CH CF3 H Me2,6-diCl—Ph (CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl) 565.43 387. CHnPr H Me 2,6-diCl—Ph (CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl) 539.5388. CH Me H Me 2,6-diCl—Ph (CH2)2—NH-(1-benzoyl-piperidin-4-yl) 646.88389. CH Me H Me 2,6-diCl—Ph (CH2)2—NH-(1-Bn-piperidin-4-yl) 523.51 390.N Me H Me 2,6-diCl—Ph (CH2)2—NH-(1-Bn-piperidin-4-yl) 524.5 391. CH Me HMe 2,6-diCl—Ph (CH2)2—NH-(1-Bn-pyrrolidin-3-yl) 509.49 392. CH Me H Me2,6-diCl—Ph (CH2)2—NH-(1-Et-piperidin-3-yl) 461.4 393. CH Me H Me2,6-diCl—Ph (CH2)2—NH-(1-Et-piperidin-4-yl) 534.36 394. CH Me H Me2,6-diCl—Ph (CH2)2—NH-(1-Me-piperidin-4-yl) 447.41 395. CH Me H Me2,6-diCl—Ph (CH2)2—NH-(4-(1-azetidino)-cHex) 487.5 396. CH Me H Me2,6-diCl—Ph (CH2)2—NH-(4-(1-morpholino)-cHex) 503.5 397. CH Me H Me2,6-diCl—Ph (CH2)2—NH-(4-(1-piperidino)-cHex) 515.5 398. CH Me H Me2,6-diCl—Ph (CH2)2—NH-(4-(1-pyrrolidino)-cHex) 647.35 399. CH Me H Me2,6-diCl—Ph (CH2)2—NH-(4-(NH—(CH2)2—OH)-cHex) 491.47 400. CH Me H Me2,6-diCl—Ph (CH2)2—NH-(4-(NH—CH2-2-pyridyl)-cHex) 538.53 401. CH Me H Me2,6-diCl—Ph (CH2)2—NH-(4-(NH-iBu)-cHex) 503.52 402. CH Me H Me2,6-diCl—Ph (CH2)2—NH-(4-(NHEt)-cHex) 460.4 403. CH Me H Me 2,6-diCl—Ph(CH2)2—NH-(4-(NHMe)-cHex) 607.28 404. CH iPr H Me 2,6-diCl—Ph(CH2)2—NH-(4-CF3-cHex) 528.5 405. CH Me H Me 2,6-diCl—Ph(CH2)2—NH-(4-ethyleneketal-cHex) 490.44 406. CH Me H Me 2,6-diCl—Ph(CH2)2—NH-(4-OH-cHex) 448.4 407. CH Me H Me 2,6-diCl—Ph(CH2)2—NH-(4-oxo-cHex) 446.38 408. N Me H Me 2,6-diCl—Ph(CH2)2—NH-(4-trans-OH-cHex) 449.4 409. CH Me H Me 2,6-diCl—Ph(CH2)2—NH-(6,7-diOMe-1,2,3,4-tetrahydronaphthalen-2-yl) 540.5 410. CH MeH Me 2,6-diCl—Ph (CH2)2-NH-(8-aza-8-methylbicyclo[3.2.1]octan-3-yl)459.43 411. CH Me H Me 2,6-diCl—Ph (CH2)2—NH-(tetrahydropyran-4-yl)434.37 412. CH iPr H Me 2,6-diCl—Ph (CH2)2—NH-(tetrahydropyran-4-yl)462.4 413. CH CF3 H Me 2,6-diCl—Ph (CH2)2—NH-(tetrahydropyran-4-yl)488.34 414. CH CF3 H Me 2,6-diCl—Ph(CH2)2—NH-(trans-1-CF3-cyclohexan-4-yl) 554.37 415. CH Me H Me2,6-diCl—Ph (CH2)2—NH-2,2,6,6-tetramethylpiperidin-4-yl 489.5 416. CH MeH Me 2,6-diCl—Ph (CH2)2—NH—CHMe—CH2-(3-OMe-4-(O—(CH2)2—NMe2)—Ph) 585.6417. CH Me H Me 2,6-diCl—Ph (CH2)2—NH—CHMe—CH2-(3-OMe-4-OH—Ph) 514.46418. N Me H Me 2,6-diCl—Ph (CH2)2—NH-cPent 449.4 419. CH Me H Me2,6-diCl—Ph (CH2)2—NH-piperidin-4-yl 433.4 420. CH Me H Me 2,6-diCl—Ph(CH2)2—NH-quinolin-2-yl 477.40 421. CH Me H Me 2,6-diCl—Ph(CH2)2—NH-quinuclidin-3-yl 459.4 422. CH Me H Me 2,6-diCl—PhCH2—CHEt—NH-(1-Ac-piperidin-4-yl) 503.48 423. CH Me H Me 2,6-diCl—PhCH2—CHEt—NH-(tetrahydropyran-4-yl) 462.43 424. CH nPr H Me 2,6-diCl—PhCH2—CHMe—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl) 553.5 425. CH Et H Me2,6-diCl—Ph CH2—CHMe—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl) 539.5 426.CH Me H Me 2,6-diCl—Ph CH2—CHMe—NH-(1-Bn-piperidin-4-yl) 537.53 427. CHMe H Me 2,6-diCl—Ph CH2—CHMe—NH-(tetrahydropyran-4-yl) 448.4 428. CH MeH Me 2,6-diCl—Ph CHEt—CH2—NH-(tetrahydropyran-4-yl) 462.4 429. CH Me HMe 2,6-diCl—Ph CHEt—CH2—NH-(tetrahydropyran-4-yl) 503.5 430. CH Me H Me2,6-diCl—Ph CHMe—CHMe—NH-(1-Bn-piperidin-4-yl) 551.57 431. CH Me H Me2,6-diCl—Ph CHMe—CHMe—NH-(tetrahydropyran-4-yl) 462.43 432. CH Me H Me2,6-diMe-3,5-diBr-4-OCF3—Ph (CH2)2—NH-(tetrahydropyran-4-yl) 634.6 433.CH Me H Me 2,6-diMe-4-Cl—Ph(CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl) 505.06 434. CH Me H Me2,6-diMe-4-Cl—Ph (CH2)2—NH-(1-Bn-piperidin-4-yl) 517.12 435. CH Me H Me2,6-diMe-4-Cl—Ph (CH2)2—NH-(1-COOEt-piperidin-4-yl) 499.0 436. CH Me HMe 2,6-diMe-4-Cl—Ph (CH2)2—NH-(4-COOH-cHexl) 470.01 437. CH Me H Me2,6-diMe-4-CN—Ph (CH2)2—NH-(tetrahydropyran-4-yl) 418.53 438. CH Me H Me2,6-diMe-4-OCF3-5-Br—Ph (CH2)2—NH-(tetrahydropyran-4-yl) 556.4 439. CHMe H Me 2,6-diMe-4-OCF3—Ph(CH2)2—NH-(1-(5-Et-pyrimidin-2-yl)-piperidin-4-yl) 582.66 440. CH Me HMe 2,6-diMe-4-OCF3—Ph (CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl)554.61 441. CH Me H Me 2,6-diMe-4-OCF3—Ph(CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl) 536.62 442. CH Me H Me2,6-diMe-4-OCF3—Ph (CH2)2—NH-(2F-cPent) 479.53 443. CH Me H Me2,6-diMe-4-OCF3—Ph (CH2)2—NH-(tetrahydropyran-4-yl) 477.52 444. CH Me HMe 2,6-diMe-4-OCF3—Ph (CH2)2—NH-(tetrahydropyran-4-yl) 459.53 445. CH MeH Me 2,6-diMe-4-OEt—Ph(CH2)2—NH-(1-(2-Cl-pyrimidin-5-yl)-piperidin-4-yl) 549.11 446. CH Me HMe 2,6-diMe-4-OEt—Ph (CH2)2—NH-(1-(2-F-pyridin-6-yl)-piperidin-4-yl)531.67 447. CH Me H Me 2,6-diMe-4-OEt—Ph(CH2)2—NH-(1-(2-OMe-pyridin-5-yl)-piperidin-4-yl) 543.70 448. CH Me H Me2,6-diMe-4-OEt—Ph (CH2)2—NH-(1-(3,6-diMe-pyrazin-2-yl)-piperidin-4-yl)542.72 449. CH Me H Me 2,6-diMe-4-OEt—Ph(CH2)2—NH-(1-(4-Me-pyridin-2-yl)-piperidin-4-yl) 527.70 450. CH Me H Me2,6-diMe-4-OEt—Ph (CH2)2—NH-(1-(4-OMe-pyrimidin-2-yl)-piperidin-4-yl)544.69 451. CH Me H Me 2,6-diMe-4-OEt—Ph(CH2)2—NH-(1-(5-CF3-pyridin-2-yl)-piperidin-4-yl) 581.68 452. CH Me H Me2,6-diMe-4-OEt—Ph (CH2)2—NH-(1-(5-F-pyrimidin-2-yl)-piperidin-4-yl)532.66 453. CH Me H Me 2,6-diMe-4-OEt—Ph(CH2)2—NH-(1-(6-Cl-pyridazin-3-yl)-piperidin-4-yl) 549.11 454. CH Me HMe 2,6-diMe-4-OEt—Ph (CH2)2—NH-(1-(6-Me-pyridin-2-yl)-piperidin-4-yl)527.70 455. CH Me H Me 2,6-diMe-4-OEt—Ph(CH2)2—NH-(1-(6-OMe-pyridin-2-yl)-piperidin-4-yl) 543.70 456. CH Me H Me2,6-diMe-4-OEt—Ph (CH2)2—NH-(1-(pyridin-2-yl)-piperidin-4-yl) 513.68457. CH Me H Me 2,6-diMe-4-OEt—Ph(CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl) 514.67 458. CH Me H Me2,6-diMe-4-OEt—Ph (CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl) 542.72459. CH Me H Me 2,6-diMe-4-OEt—Ph(CH2)2—NH-(1-(pyrimidin-5-yl)-piperidin-4-yl) 514.67 460. CH Me H Me2,6-diMe-4-OEt—Ph (CH2)2—NH-(1-(thiazol-2-yl)-piperidin-4-yl) 519.71461. CH Me H Me 2,6-diMe-4-OEt—Ph (CH2)2—NH-(4-ethyleneketal-cHex)493.64 462. CH Me H Me 2,6-diMe-4-OEt—Ph (CH2)2—NH-(4-oxo-cHex) 449.59463. CH Me H Me 2,6-diMe-4-OH—Ph(CH2)2—NH-(1-(2-F-pyridin-6-yl)-piperidin-4-yl) 503.61 464. CH Me H Me2,6-diMe-4-OMe—Ph (CH2)2—NH-(1-(2-OMe-pyridin-6-yl)-piperidin-4-yl)529.68 465. CH Me H Me 2,6-diMe-4-OMe—Ph(CH2)2—NH-(1-(4-CF3-pyrimidin-2-yl)-piperidin-4-yl) 568.64 466. CH Me HMe 2,6-diMe-4-OMe—Ph (CH2)2—NH-(1-(5-Et-pyrimidin-2-yl)-piperidin-4-yl)528.7 467. CH Me H Me 2,6-diMe-4-OMe—Ph(CH2)2—NH-(1-(5-F-pyrimidin-2-yl)-piperidin-4-yl) 518.63 468. CH Me H Me2,6-diMe-4-OMe—Ph (CH2)2—NH-(1-(6-F-2-pyridyl)-piperidin-4-yl) 517.64469. CH Me H Me 2,6-diMe-4-OMe—Ph(CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl) 500.64 470. CH Me H Me2,6-diMe-4-OMe—Ph (CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl) 486.61471. N Me H Me 2,6-diMe-4-OMe—Ph(CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl) 501.63 472. CH Me H Me2,6-diMe-4-OMe—Ph (CH2)2—NH-(1-(thiazol-2-yl)-piperidin-4-yl) 505.68473. CH Me H Me 2,6-diMe-4-OMe—Ph (CH2)2—NH-(1-Bn-piperidin-4-yl) 512.7474. CH Me H Me 2,6-diMe-4-OMe—Ph (CH2)2—NH-(1-COOEt-piperidin-4-yl)493.64 475. CH Me H Me 2,6-diMe-4-OMe—Ph (CH2)2—NH-(1-Et-piperidin-3-yl)450.62 476. CH Me H Me 2,6-diMe-4-OMe—Ph (CH2)2—NH-(1-Et-piperidin-4-yl)450.4 477. CH Me H Me 2,6-diMe-4-OMe—Ph(CH2)2—NH-(1-formyl-piperidin-4-yl) 451.3 478. CH Me H Me2,6-diMe-4-OMe—Ph (CH2)2—NH-(1-Me-piperidin-4-yl) 436.4 479. CH Me H Me2,6-diMe-4-OMe—Ph (CH2)2—NH-(1-SO2Me-piperidin-4-yl) 500.66 480. CH Me HMe 2,6-diMe-4-OMe—Ph (CH2)2—NH-(2-Me-tetrahydrofuran-3-yl) 423.55 481.CH Me H Me 2,6-diMe-4-OMe—Ph (CH2)2—NH-(2F-cPent) 425.6 482. CH Me H Me2,6-diMe-4-OMe—Ph (CH2)2—NH-(4-(1-morpholino)-cHex) 520.71 483. CH Me HMe 2,6-diMe-4-OMe—Ph (CH2)2—NH-(4-(1-piperidino)-cHex) 518.74 484. CH MeH Me 2,6-diMe-4-OMe—Ph (CH2)2—NH-(4-(1-pyrrolidino)-cHex) 490.68 485. CHMe H Me 2,6-diMe-4-OMe—Ph (CH2)2—NH-(4-(1-pyrrolidino)-cHex) 504.71 486.CH Me H Me 2,6-diMe-4-OMe—Ph (CH2)2—NH-(4-(NH—CH2-2-pyridyl)-cHex)541.73 487. CH Me H Me 2,6-diMe-4-OMe—Ph(CH2)2—NH-(4-(NH—CH2-4-pyridyl)-cHex) 541.73 488. CH Me H Me2,6-diMe-4-OMe—Ph (CH2)2—NH-(4-(NH-iBu)-cHex) 492.70 489. CH Me H Me2,6-diMe-4-OMe—Ph (CH2)2—NH-(4-NiBu—NSO2—Me)-cHex) 570.79 490. CH Me HMe 2,6-diMe-4-OMe—Ph (CH2)2—NH-(4-(NMe—NiBu)-cHex0 506.73 491. CH Me HMe 2,6-diMe-4-OMe—Ph (CH2)2—NH-(4-ethyleneketal-cHex) 479.61 492. CH MeH Me 2,6-diMe-4-OMe—Ph (CH2)2—NH-(4-NHiBu-cHex) 506.73 493. CH Me H Me2,6-diMe-4-OMe—Ph (CH2)2—NH-(4-NHSO2-Me-cHex) 514.68 494. CH Me H Me2,6-diMe-4-OMe—Ph (CH2)2—NH-(4-oxo-cHex) 435.4 495. CH Me H Me2,6-diMe-4-OMe—Ph (CH2)2—NH-(4,4-diMe-cHex) 449.63 496. CH Me H Me2,6-diMe-4-OMe—Ph (CH2)2—NH-(4,4-dioxo-tetrahydrothian-yl) 471.62 497.CH Me H Me 2,6-diMe-4-OMe—Ph (CH2)2—NH-(tetrahydropyran-4-yl) 439.63498. N Me H Me 2,6-diMe-4-OMe—Ph (CH2)2—NH-(trans-4-COOet-cHex) 494.63499. CH Me H Me 2,6-diMe-4-OMe—Ph (CH2)2—NH-(trans-4-COOEt-cHex) 493.64500. CH Me H Me 2,6-diMe-4-OMe—Ph (CH2)2—NH-(trans-4-COOH-cHex) 465.59501. CH Me H Me 2,6-diMe-4-OMe—Ph (CH2)2—NH-cyclohex-3-enyl 419.57 502.CH Me H Me 2,6-diMe-4-OMe—Ph (CH2)2—NH-piperidin-4-yl 422.5 503. CH Me HMe 2,6-diMe-4-OMe—PhCH2—CHMe—NH-(1-(5-Et-pyrimidin-2-yl)-piperidin-4-yl) 542.70 504. CH Me HMe 2,6-diMe-4-OMe—Ph CH2—CHMe—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl)514.68 505. CH Me H Me 2,6-diMe-4-OMe—PhCH2—CMe2—NH-(1-(5-Et-pyrimidin-2-yl)-piperidin-4-yl) 556.7 506. CH Me HMe 2,6-diMe-4-tBu—Ph (CH2)2—NH-(tetrahydropyran-4-yl) 449.64 507. CH EtH Me 2,6-diMe—Ph (CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl) 484.65508. CH Et H Me 2,6-diMe—Ph(CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl) 484.65 509. CH nPr H Me2,6-diMe—Ph (CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl) 498.7 510. CHMe H Me 2,6-diMe—Ph (CH2)2—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl) 470.6511. CH Et H Me 2,6-diMe—Ph (CH2)2—NH-(1-Ac-piperidin-4-yl) 448.62 512.CH Et H Me 2,6-diMe—Ph (CH2)2—NH-(1,2,3,4-tetrahydro-naphthalen-2-yl)453.6 513. CH Et H Me 2,6-diMe—PhCH2—CHMe—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl) 498.7 514. CH nPr H Me2,6-diMe—Ph CH2—CHMe—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl) 512.7 515.CH me H Me 2,6-diMe—Ph CH2—CHMe—NH-(1-(pyrimidin-2-yl)-piperidin-4-yl)484.7 516. CH Et H Me 2,6-diMe—PhCH2—CHMe—NH-(1,2,3,4-tetrahydro-naphthalen-2-yl) 467.7 517. CH Me H Me2,6-diOMe—Ph (CH2)2—NH-(1-Et-piperidin-4-yl) 452.4 518. CH Me H Me2,6-diOMe—Ph (CH2)2—NH-(4-ethyleneketal-cHex) 481.59 519. CH Me H Me2,6-diOMe—Ph (CH2)2—NH-(4-oxo-cHex) 437.3 520. CH Me H Me 2,6-diOMe—Ph(CH2)2—NH-(tetrahydropyran-4-yl) 425.52

[0233] The pharmaceutical utility of compounds of this invention areindicated by the following assays for human NPY-1 receptor activity.

[0234] Assay for Human NPY-1 Receptor Binding Activity

[0235] Compounds are assayed for activity using the following method:Baculovirus-infected Sf9 cells expressing recombinant human NPY-1receptors are harvested at 42-48 hours at which time batches of 500 mLof cell suspension are pelleted by centrifugation. Each pellet isre-suspended in 30 mL of lysis buffer (10 mM HEPES, 250 mM sucrose, 0.5gg/mL leupeptin, 2 μg/mL Aprotonin, 200 μM PMSF and 2.5 mM EDTA, pH 7.4)and gently homogenized by 50 strokes using a dounce homogenizer. Thehomogenate is centrifuged at 4° C. for 10 minutes at 536× g to pelletthe nuclei. The supernatant is collected into a fresh tube andcentrifuged twice in the same buffer at 48,000× g for 40 minutes. Thefinal pellet was re-suspended in 10 mL of PBS containing 5 mM EDTA bydounce homogenization and stored in aliquots at −80° C.

[0236] Purified membranes are washed by PBS and re-suspended by gentlepipetting in binding buffer (50 mM Tris(HCl), 5 mM KCl, 120 mM NaCl, 2mM CaC12, 1 mM MgCl2, 0.1% bovine serum albumin (BSA), pH 7.4).Membranes (5 μg) are added to siliconized (Sigmacote, Sigma)polypropylene tubes in addition to 0.050 nM [125I]NPY (porcine) forcompetition analysis or 0.010-0.500 nM [125I]NPY (porcine) forsaturation analysis. For evaluation of guanine nucleotide effects onreceptor affinity, GTP is added at a final concentration of 100 μM. Colddisplacers are added at concentrations ranging from 10-12 M to 10-6 M toyield a final volume of 0.250 mL. Nonspecific binding is determined inthe presence of 1 μM NPY (human) and accounts for less than 10% of totalbinding. Following a 2 hour incubation at room temperature, the reactionis terminated by rapid vacuum filtration. Samples are filtered overpresoaked GF/C Whatman filters (1.0% polyethyleneimine for 2 hours) andrinsed 2 times with 5 mL cold binding buffer lacking BSA. Remainingbound radioactivity is measured by gamma counting. To estimate the Bmax,Kd and Ki, the results of binding experiments are analyzed usingSigmaPlot software (Jandel). The binding affinity for the compounds ofthe invention, expressed as a Ki value, ranges from about 0.1 nanomolarto about 10 micromolar. The most active compounds of the invention havea Ki of less than 100 nanomolar and a binding selectivity of >100-foldrelative to other G-protein coupled receptors, including NPY₅ and CRF₁receptors.

[0237] hNPY 1-36 Induced GTPγ³⁵S Binding at Human NPY Y1 ReceptorsCo-Expressed With Gαi2, Gβ1I and Gγ2 in Sf9 Cells.

[0238] Agonist induced GTPγ³⁵ S binding by G-protein coupled receptors(GPCR) provides a functional measure of G-protein activation. This assayhas been widely used for many GPCR's and offers the possibility todistinguish agonists from antagonists and to determine potency andefficacy of agonists for a given GPCR [Thomas et al., 1995; O'Boyle andLawler, 1995]. GTPγ³⁵ S binding activity was measured using amodification of a previously described method [Wieland and Jacobs,1994]. Log-phase Sf9 cells were co-infected with separate baculoviralstocks encoding the hNPY Y1 receptor and the G-protein subunits αi2, β1,and γ2 followed by culturing in Hink's TNM-FH insect medium supplementedGrace's with 4.1 mM L-Gln, 3.3 g/L LAH, 3.3 g/L ultrafiltered yeastolateand 10% heat-inactivated fetal bovine serum at 27° C. 72 hours postinfection, a sample of cell suspension was analyzed for viability bytrypan blue dye exclusion, and the remaining Sf9 cells were harvestedvia centrifugation (3000 rpm/10 min/4° C.). Each pellet was re-suspendedin homogenization buffer (10 mM HEPES, 250 mM sucrose, 0.5 μg/mlleupeptin, 2 μg/ml Aprotonin, 200 μM PMSF and 2.5 mM EDTA, pH 7.4) andhomogenized using a Polytron (setting 5 for 30 seconds). The homogenatewas centrifuged at 4° C. for 10 minutes at 536× g to pellet the nuclei.The supernatant was collected into a fresh tube and centrifuged twice inthe same buffer at 48,000× g for 40 minutes. The final pellet for eachmembrane preparation was re-suspended in DPBS containing 5 mM EDTA andstored in aliquots at −80° C. On the day of the assay, thawed membranehomogenates were re-suspended in assay buffer (50 mM Tris pH 7.0, 120 mMNaCl, 2 mM MgCl₂, 2 mM EGTA, 0.1% BSA, 0.1 mM bacitracin, 100 KIU/mLAprotinin, 5 μM GDP) and added to reaction tubes at a concentration of30 μg/reaction tube. After adding test compounds at concentrationsranging from 10⁻¹¹M to 10⁻⁵M, reactions were initiated by the additionof both 100 pM GTPγ³⁵S and hNPY1-36 ranging in concentration from 0.001nM to 1.0 μM (final volume of 0.250 ml). Following a 30 minuteincubation at RT°, the reaction was terminated by vacuum filtration overGF/C filters (Pre-soaked in wash buffer, 0.1% BSA) with ice-cold washbuffer (50 mM Tris pH 35 7.0, 120 mM NaCl). Bound GTPγ³⁵S was determinedby liquid scintillation spectrometry. Non-specific binding was definedby 10 FM GTPγ³⁵S and represented less than 5 percent of total binding.To estimate the EC₅₀, IC₅₀ and K_(i), the results of GTPγ³⁵S bindingexperiments were analyzed using SigmaPlot software (Jandel). The bindingaffinity for the compounds of the invention, expressed as a Ki value,ranges from about 0.1 nanomolar to about 10 micromolar. The most activecompounds of the invention have a Ki of less than 100 nanomolar.

[0239] Food Deprivation Model

[0240] Subjects.

[0241] Experimentally naive and experienced male Sprague-Dawley rats(Sasco, St. Louis, Mo.) weighing 210-300g at the beginning of theexperiment were used. Animals were id triple-housed in stainless steelhanging cages in a temperature (22 C±2 ) and humidity (40-70% RH)controlled animal facility with a 12:12 hour light-dark cycle. Food(Standard Rat Chow, PMI Feeds Inc., #5012) and water were available adlibitum.

[0242] Apparatus.

[0243] Consumption data was collected while the animals were housed inNalgene Metabolic cages (Model #650-0100). Each cage was comprised ofsubassemblies made of clear polymethlypentene (PMP), polycarbonate (PC),or stainless steel (SS). All parts disassemble for quick and accuratedata collection and for cleaning. The entire cylinder- shaped plasticand SS cage rests on a SS stand and houses one animal.

[0244] The animal is contained in the round Upper Chamber (PC) assembly(12 cm high and 20 cm in diameter) and rests on a SS floor. Twosubassemblies are attached to the Upper Chamber. The first assemblyconsists of a SS feeding chamber (10 cm long, 5 cm high and 5 cm wide)with a PC feeding drawer attached to the bottom. The feeding drawer hastwo compartments: a food storage compartment with the capacity forapproximately 50 g of pulverized rat chow, and a food spillagecompartment. The animal is allowed access to the pulverized chow by anopening in the SS floor of the feeding chamber. The floor of the feedingchamber does not allow access to the food dropped into the spillagecompartment.

[0245] The second assembly includes a water bottle support, a PC waterbottle (100 ml capacity) and a graduated water spillage collection tube.The water bottle support funnels any spilled water into the waterspillage collection tube.

[0246] The lower chamber consists of a PMP separating cone, PMPcollection funnel, PMP fluid (urine) collection tube, and a PMP solid(feces) collection tube. The separating cone is attached to the top ofthe collection funnel, which in turn is attached to the bottom of theUpper Chamber. The urine runs off the separating cone onto the walls ofthe collection funnel and into the urine collection tube. The separatingcone also separates the feces and funnels it into the feces collectiontube.

[0247] Food consumption, water consumption, and body weight weremeasured with an Ohaus Portable Advanced scale (±0.1 g accuracy).

[0248] Procedure.

[0249] Prior to the day of testing, animals were habituated to thetesting apparatus by placing each animal in a Metabolic cage for 1 hour.On the day of the experiment, animals that were food deprived theprevious night were weighed and assigned to treatment groups.Assignments were made using a quasi-random method utilizing the bodyweights to assure that the treatment groups had similar average bodyweight. Animals were then administered either vehicle (0.5% methylcellulose, MC) or drug. At that time, the feeding drawer filled withpulverized chow, the filled water bottle, and the empty urine and fecescollection tubes were weighed. Two hours after drug treatment, eachanimal was weighed and placed in a Metabolic Cage. Following a one hourtest session, animals were removed and body weight obtained. The foodand water containers were then weighed and the data recorded.

[0250] Drugs.

[0251] Drug (suspended in 0.5% MC) or 0.5% MC was administered orally(PO) using a gavage tube connected to a 3 or 5ml syringe at a volume of10 ml/kg. Drug was made into a homogenous suspension by stirring andultrasonicating for at least 1 hour prior to dosing.

[0252] Statistical Analyses.

[0253] The means and standard errors of the mean (SEM) for foodconsumption, water consumption, and body weight change are presented.One-way analysis of variance using Systat (5.2.1) was used to test forgroup differences. A significant effect is defined as having a p valueof <0.05.

[0254] The following parameters are defined: Body weight change is thedifference between the body weight of the animal immediately prior toplacement in the metabolic cage and its body weight at the end of theone hour test session. Food consumption is the difference in the weightof the food drawer prior to testing and the weight following the 1 hourtest session. Water consumption is the difference in the weight of thewater bottle prior to testing and the weight following the 1 hour testsession. The most potent compounds of the invention significantly reducefood intake and body weight gain.

[0255] The invention and the manner and process of making and using it,are now described 15-in such full, clear, concise and exact terms as toenable any person skilled in the art to which it pertains, to make anduse the same. It is to be understood that the foregoing describespreferred embodiments of the present invention and that modificationsmay be made therein without departing from the spirit or scope of thepresent invention as set forth in the claims. To particularly point outand distinctly claim the subject matter regarded as invention, thefollowing claims conclude this specification.

1 1 1 1605 DNA Homo sapiens 1 ccttctttaa tgaagcagga gcgaaaaagacaaattccaa agaggattgt tcagttcaag 60 ggaatgaaga attcagaata attttggtaaatggattcca atatggggaa taagaataag 120 ctgaacagtt gacctgcttt gaagaaacatactgtccatt tgtctaaaat aatctataac 180 aaccaaacca atcaaaatga attcaacattattttcccag gttgaaaatc attcagtcca 240 ctctaatttc tcagagaaga atgcccagcttctggctttt gaaaatgatg attgtcatct 300 gcccttggcc atgatattta ccttagctcttgcttatgga gctgtgatca ttcttggtgt 360 ctctggaaac ctggccttga tcataatcatcttgaaacaa aaggagatga gaaatgttac 420 caacatcctg attgtgaacc tttccttctcagacttgctt gttgccatca tgtgtctccc 480 ctttacattt gtctacacat taatggaccactgggtcttt ggtgaggcga tgtgtaagtt 540 gaatcctttt gtgcaatgtg tttcaatcactgtgtccatt ttctctctgg ttctcattgc 600 tgtggaacga catcagctga taatcaaccctcgagggtgg agaccaaata atagacatgc 660 ttatgtaggt attgctgtga tttgggtccttgctgtggct tcttctttgc ctttcctgat 720 ctaccaagta atgactgatg agccgttccaaaatgtaaca cttgatgcgt acaaagacaa 780 atacgtgtgc tttgatcaat ttccatcggactctcatagg ttgtcttata ccactctcct 840 cttggtgctg cagtattttg gtccactttgttttatattt atttgctact tcaagatata 900 tatacgccta aaaaggagaa acaacatgatggacaagatg agagacaata agtacaggtc 960 cagtgaaacc aaaagaatca atatcatgctgctctccatt gtggtagcat ttgcagtctg 1020 ctggctccct cttaccatct ttaacactgtgtttgattgg aatcatcaga tcattgctac 1080 ctgcaaccac aatctgttat tcctgctctgccacctcaca gcaatgatat ccacttgtgt 1140 caaccccata ttttatgggt tcctgaacaaaaacttccag agagacttgc agttcttctt 1200 caacttttgt gatttccggt ctcgggatgatgattatgaa acaatagcca tgtccacgat 1260 gcacacagat gtttccaaaa cttctttgaagcaagcaagc ccagtcgcat ttaaaaaaat 1320 caacaacaat gatgataatg aaaaaatctgaaactactta tagcctatgg tcccggatga 1380 catctgttta aaaacaagca caacctgcaacatactttga ttacctgttc tcccaaggaa 1440 tggggttgaa atcatttgaa aatgactaagattttcttgt cttgcttttt actgcttttg 1500 ttgtagttgt cataattaca tttggaacaaaaggtgtggg ctttggggtc ttctggaaat 1560 agttttgacc agacatcttt gaagtgctttttgtgaattt accag 1605

What is claimed is:
 1. A compound of the formula

or a pharmaceutically acceptable salt, hydrate, or prodrug thereof,wherein: X is N or CR¹⁴; R¹ is selected from H, C₁-C₆ alkyl, C₃-C₁₀cycloalkyl, (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, cyano, halo, C₁-C₆ haloalkyl, OR⁷, C₁-C₆ alkyl-OR⁷; C₁-C₆cyanoalkyl, NR⁸R⁹, C₁-C₆ alkyl-NR⁸R⁹; P² is H, C₁-C₆ alkyl whichoptionally forms a C₃-C₆ aminocarbocycle or a C₂-C₅ aminoheterocyclewith A or B, each of which is optionally substituted with R⁷, C₃-C₁₀cycloalkyl, or (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl; or R² and R⁶ jointlywith the 2 nitrogen atoms to which they are bound, form a C₂-C₅aminoheterocycle optionally substituted with R⁷, or R² and A jointlyform a C₃-C₆ aminocarbocycle or a C₂-C₅ aminoe heterocycle optionallysubstituted at with R⁷; A represents an alkyl chain of 1,2, or 3 carbonatoms which is optionally mono- or di-substituted at each carbon withsubstituents independently selected from C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl,(C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, cyano,halo, C₁-C₆ haloalkyl, OR⁷, C₁-C₆ alkyl-OR⁷; C₁-C₆ cyanoalkyl, NR⁸R⁹,and C₁-C₆ alkyl-NR⁸R⁹, or A and B jointly form a C₃-C₆ carbocycle,optionally substituted at each atom with R⁷; B represents an alkyl chainof 1,2 or 3 carbons atoms, which is optionally mono- or di-substitutedat each carbon with substituents independently selected from C₁-C₆alkyl, C₃-C₁₀ cycloalkyl, (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, cyano, halo, C₁-C₆ haloalkyl, OR⁷, C₁-C₆alkyl-OR⁷; C₁-C₆ cyanoalkyl, NR⁸R⁹, and C₁-C₆ alkyl-NR⁸R⁹, or B and R²jointly form a C₃-C₆ aminocarbocycle, which is optionally substituted ateach atom with R⁷, or B and R⁶ jointly form a C₃-C₆ aminocarbocycle,which is optionally substituted at each atom with R⁷; R³ is selectedfrom H, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, cyano, halo, C₁-C₆ haloalkyl, OR⁷, C₁-C₆alkyl-OR⁷, C₁-C₆ cyanoalkyl, NR⁸R⁹, C₁-C₆ alkyl-NR⁸R⁹; R⁴ is selectedfrom aryl or heteroaryl, each of which is substituted with 1 to 5substituents independently selected from C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl,C₃-C₁₀ cycloalkenyl, (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, C₁-C₆ alkenyl,C₁-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, trifluromethylsulfonyl, OR⁷,C₁-C₆ alkyl-OR⁷, NR⁸R⁹, C₁-C₆ alkyl-NR⁸R⁹, CONR⁸R⁹, C₁-C₆ alkyl-CONR⁵R⁹,COOR⁷, C₁-C₆ alkyl-COOR⁷, CN, C₁-C₆ alkyl-CN, SO₂NR⁸R⁹, SO₂R⁷, aryl,heteroaryl, heterocycloalkyl, 3-, 4-, or 5-(2-oxo-1,3-oxazolidinyl),wherein at least one of the positions ortho or para to the point ofattachment of the aryl or heteroaryl ring to the pyrazole issubstituted; R⁵ is selected from: C₁-C₆ alkyl, (C₃-C₁₀ cycloalkyl) C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, each of which is substituted with 1to 5 groups independently selected at each occurrence from halo, C₁-C₂haloalkyl, oxo, OR⁷, cyano, NR⁸R⁹, CONR⁸R⁹, COOR⁷, SO₂NR⁸R⁹, SO₂R⁷,NR¹¹COR¹², NR¹¹SO₂R⁷; Aryl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl,aryl(C₅-C₈)cycloalkyl, or heteroaryl(C₅-C₈)cycloalkyl, each of which isoptionally substituted with 1 to 5 substituents independently selectedat each occurrence from C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀cycloalkenyl, (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, C₁-C₆ alkenyl, halogen,C₁-C₆ haloalkyl, trifluromethylsulfonyl, OR⁷, NR⁸R⁹, C₁-C₆ alkyl-OR⁷,C₁-C₆ alkyl-NR⁸R⁹, CONR⁸R⁹, COOR⁷, CN, SO₂NR⁸R⁹, SO₂R⁷, aryl,heteroaryl, heterocycloalkyl, 3-, 4-, or 5-(2-oxo-1,3-oxazolidinyl),wherein any 2 adjacent substituents may be take together to form aC₃-C₁₀ cycloalkyl ring, a C₃-C₁₀ cycloalkenyl ring or a heterocycloalkylring; C₃-C₁₀ cycloalkyl or C₂-C₉ heterocycloalkyl containing one, two,or three O, S, or N atoms, each of which is optionally substituted with1 to 6 substituents independently selected from C₁-C₆ alkyl, C₃-C₁₀cycloalkyl, C₃-C₁₀ cycloalkenyl, (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, C₁-C₆alkenyl, oxo, halogen, C₁-C₆ haloalkyl, OR⁷, NR⁸R⁹, (with the provisothat when two OR⁷ or NR⁸R⁹ substituents are geminally located on thesame carbon R⁷ is not H and the geminally located OR⁷ or NR⁸R⁹substitutuents can be taken together to form a C₂-C₄ ketal, oxazoline,oxazolidine, imidazoline, or imidazolidine heterocycle), C₁-C₆alkyl-OR⁷, C₁-C₆ alkyl-NR⁵R⁹, CONR⁸R⁹, COOR⁷, CN, oxo, hydroximino,C₁-C₆ alkoximino, SO₂NR⁸R⁹, SO₂R⁷, heterocycloalkyl, aryl, heteroaryl,where aryl or heteroaryl is optionally substituted with 1 to 5substituents independently selected at each occurrence from C₁-C₆ alkyl,C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl, (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl,C₁-C₆ alkenyl, halogen, C₁-C₆ haloalkyl, trifluromethylsulfonyl, OR⁷,NR⁸R⁹, C₁-C₆ alkyl-OR⁷, C₁-C₆ alkyl-NR⁸R⁹, CONR⁸R⁹, COOR⁷, CN, SO₂NR⁸R⁹,SO₂R⁷, aryl, heteroaryl, heterocycloalkyl, 3-, 4-, or5-(2-oxo-1,3-oxazolidinyl), with the proviso that 2 adjacentsubstituents can optionally form together a C₃-C₁₀ cycloalkyl ring, aC₃-C₁₀ cycloalkenyl ring or a heterocycloalkyl ring; aryl or heteroaryl,optionally substituted with 1 to 5 substituents independently selectedat each occurrence from halogen, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀cycloalkenyl, (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, C₁-C₆ alkenyl, halogen,C₁-C₆ haloalkyl, trifluromethylsulfonyl, OR⁷, NR⁸R⁹, C₁-C₆ alkyl-OR⁷,C₁-C₆ alkyl-NRR⁹, CONR⁸R⁹, COOR⁷, CN, SO₂NRkR⁹, SO₂R⁷, aryl, heteroaryl,heterocycloalkyl, 3-, 4-, or 5-(2-oxo-1,3-oxazolidinyl), wherein any 2adjacent substituents may be taken together to form a C₃-C₁₀ cycloalkylring, a C₃-C₁₀ cycloalkenyl ring or a heterocycloalkyl ring; or 3- or4-piperidinyl, 3-pyrrolidinyl, 3- or 4- tetrahydropyranyl,3-tetrahydrofuranyl, 3- or 4-tetrahydropyranyl, 3-tetrahydrofuranyl, 3-or 4-tetrahydrothiopyranyl, 3- or 4-(1,1-dioxo) tetrahydrothiopyranyl,1-azabicyclo[4.4.0]decyl, 8-azabicyclo[3.2.1]octanyl, norbornyl,quinuclidinyl, indolin-2-one-3-yl, 2-(methoximino)-perhydroazepin-6-yl,each optionally substituted with 1 to 5 substituents independentlyselected at each occurrence from R⁷, C₁-C₆ alkyl-OR⁷, C₁-C₆ alkyl-NR⁸R⁹,CONR⁸R⁹, CN, COOR⁷ SO₂NR⁸R⁹, and SO₂R⁷; R⁶ is selected from H, C₁-C₆alkyl, C₃-C₁₀ cycloalkyl, (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, C₂-C₄alkenyl, aryl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl each of which isoptionally substituted with 1 to 5 substituents independently fromhalogen, C₁-C₆ haloalkyl, OR¹³, NR⁸R⁹, C₁-C₆ alkyl-OR¹³, C₁-C₆alkyl-NR⁸R⁹, CONR⁸R⁹, COOR⁷, CN, SO₂NR⁸R⁹, and SO₂R⁷; R⁷ isindependently selected at each occurrence from H, C₁-C₆ alkyl, C₃-C₁₀cycloalkyl, C₃-C₁₀ cycloalkenyl, (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, C₁-C₃haloalkyl, or heterocycloalkyl, C₁-C₈ alkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, C₁-C₈ alkanoyl, aroyl, heteroaroyl, aryl,heteroaryl, C₁-C₆ arylalkyl or C₁-C₆ heteroarylalkyl each optionallysubstituted with 1 to 5 substituents independently selected fromhalogen, C₁-C₆ haloalkyl, OR¹³, NR⁸R⁹, C₁-C₆ alkyl-OR¹³, C₁-C₆alkyl-NR⁸R⁹, CONR⁸R⁹, COOR¹³, CN, SO₂NR⁸R⁹, and SO₂R¹³, with the provisothat when R⁷ is SO₂R¹³, R¹³ cannot be H R⁸ and R⁹ are independentlyselected at each occurrence from H, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl,C₂-C₆ alkenyl, C₃-C₁₀ cycloalkenyl, C₂-C₆ alkynyl, heterocycloalkyl,C₁-C₈ alkanoyl, aroyl, heteroaroyl, aryl, heteroaryl, C₁-C₆ arylalkyl orC₁-C₆ heteroarylalkyl, or R⁸ and R⁹, taken together, can form a C₃-C₆aminocarbocycle or a C₂-C₅ aminoheterocycle each of which is optionallysubstituted with C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl,(C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, C₁-C₃ haloalkyl, or heterocycloalkyl,C₁-C₈ alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, C₁-C₈ alkanoyl,aroyl, heteroaroyl, aryl, heteroaryl, C₁-C₆ arylalkyl or C₁-C₆heteroarylalkyl; R¹¹ is selected from H, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl,(C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl; R¹² is selected from H, aryl,heteroaryl, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, (C₃-C₁₀ cycloalkyl) C₁-C₆alkyl, optionally substituted with OR⁷, NR⁸R⁹, C₃-C₆ aminocarbocycle, orC₂-C₅ aminoheterocycle; R¹³ is independently selected at each occurrencefrom H, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, with the proviso thatwhen R⁷ is SO₂R¹³, R¹³ cannot be H; and R¹⁴ is H, C₁-C₆ alkyl, C₃-C₁₀cycloalkyl, (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, C₂-C₄ alkenyl, C₂-C₄alkynyl, halo, or CN.
 2. A compound according to claim 1, wherein R⁵ isphenyl, naphthyl, 2-,3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl,triazinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, isoxazolyl,indolyl, pyrazolyl, quinolyl, isoquinolyl, 2-, 4-, or 5-thiazolyl,benzothiadiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl,2-triazinyl, 2-pyrazinyl, 2-, or 3-furanyl, 2-, or 3-thienyl, 2-, or3-benzothienyl, or 1-, 2- or 5-tetrazolyl each of which is optionallysubstituted with 1 to 5 substituents independently selected from C₁-C₆alkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl, (C₃-C₁₀ cycloalkyl) C₁-C₆alkyl, C₁-C₆ alkenyl, halogen, C₁-C₆ haloalkyl, trifluromethylsulfonyl,OR⁷, NR⁸R⁹, C₁-C₆ alkyl-OR⁷, C₁-C₆ alkyl-NR⁸R⁹, CONR⁸R⁹, COOR⁷, CN,SO₂NR⁸R⁹, SO₂R⁷, aryl, heteroaryl, heterocycloalkyl, 3-, 4-, oroxo-1,3-oxazolidinyl), wherein 2 adjacent substituents may be takentogether to form a cycloalkyl ring, a C₃-C₁₀ cycloalkenyl ring or aheterocycloalkyl ring.
 3. A compound according to claim 1, wherein X isN R¹ is H, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, or (C₃-C₁₀ cycloalkyl) C₁-C₆alkyl; and R⁶ is H, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, or (C₃-C₁₀cycloalkyl) C₁-C₆ alkyl.
 4. A compound according to claim 1, wherein Xis N; R¹ is C₁-C₆ alkyl; R² is H or C₁-C₆ alkyl; R³ is C₁-C₆ alkyl,trifluoromethyl, or C₁-C₆alkyl-O C₁-C₆alkyl; and R⁶ is H, C₁-C₆ alkyl,C₃-C₁₀ cycloalkyl, or (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl.
 5. A compoundaccording to claim 1, wherein; X is N; R¹ is C₁-C₆ alkyl; R² is H orC₁-C₆ alkyl; R³ is C₁-C₆ alkyl, trifluoromethyl, or C₁-C₆alkyl-OC₁-C₆alkyl; R⁴ is phenyl, mono, di, or trisubstituted with C₁-C₆ alkyl,C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl, (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl,C₁-C₆ alkenyl, halogen, C₁-C₆ haloalkyl, trifluromethylsulfonyl, OR⁷,C₁-C₆ alkyl-OR⁷, NR⁸R⁹, C₁-C₆ alkyl-NR⁸R⁹, CONR⁸R⁹, C₁-C₆ alkyl-CONR⁸R⁹,COOR⁷, C₁-C₆ alkyl-COOR⁷, CN, C₁-C₆ alkyl-CN, SO₂NR⁸R⁹, SO₂R⁷, aryl,heteroaryl, heterocycloalkyl, 3-, 4-, or 5-(2-oxo-1,3-oxazolidinyl),wherein at least one of the positions ortho or para to the point ofattachment of the aryl or heteroaryl ring to the pyrazole issubstituted, R⁶ is H, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, or (C₃-C₁₀cycloalkyl) C₁-C₆ alkyl; and R⁷, R⁸, and R⁹ are as defined in claim 1.6. A compound according to claim 1, wherein: X is N; R¹ is C₁-C₆ alkyl;R² is H or C₁-C₆ alkyl; R³ is C₁-C₆ alkyl, trifluoromethyl, orC₁-C₆alkyl-O C₁-C₆alkyl; R⁴ is phenyl, mono, di, or trisubstituted withC₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl, (C₃-C₁₀ cycloalkyl)C₁-C₆ alkyl, C₁-C₆ alkenyl, halogen, C₁-C₆ haloalkyl,trifluromethylsulfonyl, OR⁷, C₁-C₆ alkyl-OR⁷, NR⁸R⁹, C₁-C₆ alkyl-NR⁸R⁹,CONR⁸R⁹, C₁-C₆ alkyl-CONR⁸R⁹, COOR⁷, C₁-C₆ alkyl-COOR⁷, CN, C₁-C₆alkyl-CN, SO₂NR⁸R⁹, SO₂R⁷, aryl, heteroaryl, heterocycloalkyl, 3-, 4-,or 5-(2-oxo-1,3-oxazolidinyl), wherein at least one of the positionsortho or para to the point of attachment of the aryl or heteroaryl ringto the pyrazole is substituted, R is C₁-C₆ alkyl, C₃-C₁₀cycloalkyl,(C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, each ofwhich is substituted with 1 to 5 groups independently selected at eachoccurrence from halo, C₁-C₂ haloalkyl, OR⁷, cyano, NR⁸R⁹, CONR⁸R⁹,COOR⁷, SO₂NR⁸R⁹, SO₂R⁷, NR¹¹COR¹², NR¹¹SO₂R⁷; or 3- or 4-piperidinyl,3-pyrrolidinyl, 3- or 4-tetrahydropyranyl, 3-tetrahydrofiranyl, 3- or4-tetrahydropyranyl, 3-tetrahydrofuranyl, 3- or 4-tetrahydrothiopyranyl,3- or 4-(1,1-dioxo) tetrahydrothiopyranyl, 1-azabicyclo[4.4.0]decyl,8-azabicyclo[3.2.1]octanyl, norbomyl, quinuclidinyl, indolin-2-one-3-yl,2-(methoximino)-perhydroazepin-6-yl, each optionally substituted with 1to 5 substituents independently selected at each occurrence from R⁷,C₁-C₆ alkyl-OR⁷, C₁-C₆ alkyl-NR⁸R⁹, CONR⁸R⁹, CN, COOR⁷ SO₂NR⁸R⁹, andSO₂R⁷; R⁶ is H, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, or (C₃-C₁₀ cycloalkyl)C₁-C₆ alkyl; and R⁷, R⁸, R⁹, R¹¹, and R¹² are as defined in claim
 1. 7.A compound according to claim 1, wherein; X is CH, R¹ is H, C₁-C₆ alkyl,C₃-C₁₀ cycloalkyl, or (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl; and R⁶ is H,C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, or (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl.
 8. Acompound according to claim 1, wherein: X is CH; R¹ is C₁-C₆ alkyl; R²is H or CI-C₆ alkyl; R³ is C₁-C₆ alkyl, trifluoromethyl, or C₁-C₆alkyl-OC₁-C₆alkyl; and R⁶ is H, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, or (C₃-C₁₀cycloalkyl) C₁-C₆ alkyl.
 9. A compound according to claim 1, wherein; Xis CH; R¹ is C₁-C₆ alkyl; R² is H or C₁-C₆ alkyl; R³ is C₁-C₆ alkyl,trifluoromethyl, or C₁-C₆alkyl-O C₁-C₆alkyl; R⁴ is phenyl, mono, di, ortrisubstituted with C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl,(C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, C₁-C₆ alkenyl, halogen, C₁-C₆haloalkyl, trifluromethylsulfonyl, OR⁷, C₁-C₆ alkyl-OR⁷, NR⁸R⁹, C₁-C₆alkyl-NR⁸R⁹, CONRR⁹, C₁-C₆ alkyl-CONRR⁹, COOR⁷, C₁-C₆ alkyl-COOR⁷, CN,C₁-C₆ alkyl-CN, SO₂NRR⁹, SO₂R⁷, aryl, heteroaryl, heterocycloalkyl, 3-,4-, or 5-(2-oxo-1,3-oxazolidinyl), wherein at least one of the positionsortho or para to the point of attachment of the aryl or heteroaryl ringto the pyrazole is substituted, R⁶ is H, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl,or (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl; and R⁷, R⁸, and R⁹ are as defined inclaim
 1. 10. A compound according to claim 1, wherein: X is CH; R¹ isC₁-C₆ alkyl; R² is H or C₁-C₆ alkyl; R³ is C₁-C₆ alkyl, trifluoromethyl,or C₁-C₆alkyl-O C₁-C₆alkyl; R⁴ is phenyl, mono, di, or trisubstitutedwith C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl, (C₃-C₁₀cycloalkyl) C₁-C₆ alkyl, C₁-C₆ alkenyl, halogen, C₁-C₆ haloalkyl,trifluromethylsulfonyl, OR⁷, C₇-C₆ alkyl-OR⁷, NR⁸R⁹, C₁-C₆ alkyl-NR⁸R⁹,CONR⁸R⁹, C₁-C₆ alkyl-CONR⁸R⁹, COOR⁷, C₁-C₆ alkyl-COOR⁷, CN, C₁-C₆alkyl-CN, SO₂NRR⁹, SO₂R⁷, aryl, heteroaryl, heterocycloalkyl, 3-, 4-, or5-(2-oxo-1,3-oxazolidinyl), wherein at least one of the positions orthoor para to the point of attachment of the aryl or heteroaryl ring to thepyrazole is substituted, R⁵ is C₁-C₆ alkyl, C₃-C₁₀cycloalkyl, (C₃-C₁₀cycloalkyl) C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, each of which issubstituted with 1 to 5 groups independently selected at each occurrencefrom halo, C₁-C₂ haloalkyl, OR⁷, cyano, NR⁸R⁹, CONR⁸R⁹, COOR⁷, SO₂NR⁸R⁹,SO₂R⁷, NR¹¹COR¹², NR¹¹SO₂R⁷; or 3- or 4-piperidinyl, 3-pyrrolidinyl, 3-or 4-tetrahydropyranyl, 3-tetrahydrofuranyl, 3- or 4- tetrahydropyranyl,3-tetrahydrofuranyl, 3- or 4-tetrahydrothiopyranyl, 3- or 4-(1,1 -dioxo)tetrahydrothiopyranyl, 1-azabicyclo[4.4.0]decyl, 8-Hazabicyclo[3.2.1]octanyl, norbomyl, quinuclidinyl, indolin-2-one-3-yl,2-(methoximino)-perhydroazepin-6-yl, each optionally substituted with 1to 5 substituents independently selected at each occurrence from R⁷,C₁-C₆ alkyl-OR⁷, C₁-C₆ alkyl-NR⁸R⁹, CONR⁸R⁹, CN, COOR⁷ SO₂NR⁸R⁹, andSO₂R⁷; R⁶ is H, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, or (C₃-C₁₀ cycloalkyl)C₁-C₆ alkyl; and R⁷, R⁸, R⁹, R¹¹, and R¹² are as defined in claim
 1. 11.A method for treating eating disorders and cardiovascular disorderscomprising administering to a patient suffering from an eating disorderor cardiovascular disorder a compound according to claim
 1. 12. Apharmaceutical composition comprising a compound according to claim 1and a pharmaceutically acceptable carrier.
 13. A packaged pharmaceuticalcomposition comprising the pharmaceutical composition of claim 12 in acontainer and comprising instructions for using the composition to treata patient suffering from an eating disorder or hypertension.
 14. Amethod for localizing NPY receptors in tissue section samplescomprising: contacting with a sample of tissue a detectably-labeledcompound of claim 1 under conditions that permit binding of the compoundto the sample of tissue; washing the tissue sample to remove unboundcompound; and detecting the bound compound.
 15. The method of claim 14,wherein the compound is radiolabeled.
 16. A method of inhibiting thebinding of NPY to the NPY1 receptor, which method comprises contacting,in the presence of NPY, a solution comprising a compound of claim 1 withcells expressing the NPY1 receptor, wherein the compound is present inthe solution at a concentration sufficient to reduce levels of NPYbinding to cells expressing the NPY1 receptor in vitro.
 17. A method foraltering the signal-transducing activity of a cell surface NPY1receptor, said method comprising contacting cells expressing such areceptor with a solution comprising a compound according to claim 1,wherein the compound is present in the solution at a concentrationsufficient to reduce levels of NPY binding to cells expressing the NPY1receptor in vitro.
 18. A compound according to any one of claim Iwherein in an assay of NPY binding the compound exhibits an K_(i) of 1micromolar or less.
 19. A compound according to any one of claim 1wherein in an assay of NPY binding the compound exhibits an K_(i) of 100nanomolar or less.
 20. A compound according to any one of claim 1wherein in an assay of NPY binding the compound exhibits an K_(i) of 100nanomolar 10 nanomolar or less.
 21. A method for treating obesity orbulimia nervosa which comprises administering an effective amount of acompound according to claim 1 to a patient in need thereof.
 22. A methodfor treating hypertension which comprises administering an effectiveamount of a compound according to claim 1 to a patient in need thereof.23. A compound in accordance with formula I

wherein: X is N or CR¹⁴; R¹ is selected from H, C₁-C₆ alkyl, C₃-C₆ycloalkyl, (C₃-C₁₀ cycloalkyl) CI-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, cyano, halo, C₁-C₆ haloalkyl, OR⁷, C₁-C₆ alkyl-OR⁷; C₁-C₆cyanoalkyl, NR⁸R⁹, C₁-C₆ alkyl-NR⁸R⁹; R² is H, C₁-C₆ alkyl whichoptionally forms a C₃-C₆ aminocarbocycle or a C₂-C₅ aminoheterocyclewith A or B, each optionally substituted at each occurrence with R⁷,C₃-C₁₀ cycloalkyl, or (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl; or R² and R⁶jointly form with the 2 nitrogen atoms to which they are bound form aC₂-C₅ aminoheterocycle optionally substituted at each occurrence withR⁷; A is (CH₂)_(m), where m is 1,2 or 3 and is optionally mono- ordi-substituted on each occurrence with C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl,(C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cyano,halo, C₁-C₆ haloalkyl, OR⁷, C₁-C₆ alkyl-OR⁷; C_(1,)-C₆ cyanoalkyl,NR⁸R⁹, C₁-C₆ alkyl-NR⁸R⁹,or A and B jointly form a C₃-C₆ carbocycle,optionally substituted at each occurrence with R⁷, or, A and R² jointlyform a C₃-C₆ aminocarbocycle or a C₂-C₅ aminoheterocycle optionallysubstituted at each occurrence with R⁷; aminoheterocycle optionallysubstituted at each occurrence with R⁷; B is (CH₂)_(n), where n is 1,2or 3 and is optionally mono- or di-substituted on each occurrence withC₁-C₆ alkyl, C₃-C₁₀. cycloalkyl, (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, cyano, halo, C₁-C₆ haloalkyl, OR⁷, C₁-C₆alkyl-OR⁷; C₁-C₆ cyanoalkyl, NR⁸R⁹, and C₁-C₆ alkyl-NR⁸R⁹; or, asmentioned above, B an A jointly form a C₃-C₆ carbocycle, optionallysubstituted at each occurrence with R⁷ or, as mentioned above, B and R²jointly form a C₁-C₆ aminocarbocycle or a C₂-C₅ aminoheterocycleoptionally substituted at each occurrence with R⁷; R³ is selected fromH, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ akynyl, cyano, halo, C₁-C₆ haloalkyl, OR⁷, C₁-C₆alkyl-OR⁷, C₁-C₆ cyanoalkyl, NR⁸R⁹, C₁-C₆ alkyl-NR⁸R⁹; R⁴ is selectedfrom aryl or heteroaryl, each of which is substituted with 1 to 5substituents independently selected from C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl,C₃-C₁₀ cycloalkenyl, (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, C₁-C₆ alkenyl,C₁-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, trifluromethylsulfonyl, OR⁷,C₁-C₆ alkyl-OR⁷, NR⁸R⁹, C₁-C₆ alkyl-NR⁸R⁹, CONk⁸R⁹, C_(l)-C₆alkyl-CONR8R⁹, COOR⁷, C₁-C₆ alkyl-COOR⁷, CN, C₁-C₆ alkyl-CN, SO₂NR⁸R⁹,SO₂R⁷, aryl, heteroaryl, heterocycloalkyl, 3-, 4-, or5-(2-oxo-1,3-oxazolidinyl), wherein at least one of the positions orthoor para to the point of attachment of the aryl or heteroaryl ring to thepyrazole is substituted; R⁵is selected from: C₁-C₆ alkyl, (C₃-C₁₀cycloalkyl) C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, each of which issubstituted with 1 to 5 groups independently selected at each occurrencefrom halo, C₁-C₂ haloalkyl, oxo, OR⁷, cyano, NR⁸R⁹, CONR⁸R⁹, COOR⁷,SO₂NR⁸R⁹, SO₂R⁷, NR¹¹COR¹²,NR¹¹SO₂R⁷; Aryl(C₁-C₆)alkyl,heteroaryl(C₁-C₆)alkyl, aryl(C₅-C₈)cycloalkyl, orheteroaryl(C₅-C₈)cycloalkyl, where aryl is phenyl or naphthyl, andheteroaryl is 2-, 3- or 4-pyridyl, 2-, 4-, or 5-pyrimimidinyl,triazinyl, 1-, 2-, or 4-imidazolyl 2-, 4-, or 5-oxazolyl, isoxazolylindolyl, pyrazolyl, quinolyl, isoquinolyl, 2-, 4-, or 5-thiazolyl,benzothiadiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl,2-triazinyl, 2-pyrazinyl, 2-, or ³-furanyl, 2-, or 3-thienyl, 2-, or3-benzothienyl, or 1-, 2- or 5-tetrazolyl, each of which is optionallysubstituted with 1 to 5 substituents independently selected at eachoccurrence from C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl,(C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, C₁-C₆ alkenyl, halogen, C₁-C₆haloalkyl, trifluoromethylsulfonyl, OR⁷, NR⁸R⁹, C₁-C₆ alkyl-OR⁷, C₁-C₆alkyl-NR⁸R⁹, CONR⁸R⁹, COOR⁷, CN, SO₂NR⁸R⁹, SO₂R⁷, aryl, heteroaryl,heterocycloalkyl, 3-, 4-, or 5-(2-oxo-1,3-oxazolidinyl), wherein any 2adjacent substituents may be take together to form a C₃-C₁₀ cycloalkylring, a C₃-C₁₀ cycloalkenyl ring or a heterocycloalkyl ring; C₃-C₁₀cycloalkyl optionally substituted with 1 to 6 substituents independentlyselected from C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl,(C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, C₁-C₆ alkenyl, oxo, halogen, C₁-C₆haloalkyl, OR⁷, NR⁸R?, (with the proviso that when two OR⁷ or NR⁸R⁹substituents are geminally located on the same carbon R⁷ is not H andthe geminally located OR⁷ or NR8R⁹ substitutuents can be taken togetherto form a C₂-C₄ ketal, oxazoline, oxazolidine, imidazoline, orimidazolidine heterocycle), C₁-C₆ alkyl-OR⁷, C₁-C₆ alkyl-NR⁸R⁹, CONRR⁹,COOR⁷, CN, oxo, is hydroximino, C₁-C₆ alkoximino, SO₂NR8R⁹, SO₂R⁷,heterocycloalkyl, aryl, heteroaryl, where aryl or heteroaryl isoptionally substituted with 1 to 5 substituents independently selectedat each occurrence from C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀cycloalkenyl, (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, C₁-C₆ alkenyl, halogen,C₁-C₆ haloalkyl, trifluromethylsulfonyl, OR⁷, NR⁸R⁹, C₁-C₆ alkyl-OR⁷,C₁-C₆ alkyl-NReR⁹, CONR⁸R⁹, COOR⁷, CN, SO₂NRPR⁹, SO₂R⁷, aryl,heteroaryl, heterocycloalkyl, 3-, 4-, or 5-(2-oxo-1,3-oxazolidinyl),with the proviso that 2 adjacent substituents can optionally formtogether a C₃-C₁₀ cycloalkyl ring, a C₃-C₁₀ cycloalkenyl ring or aheterocycloalkyl ring; aryl or heteroaryl, optionally substituted with 1to 5 substituents independently selected at each occurrence fromhalogen, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl, (C₃-C₁₀cycloalkyl) C₁-C₆ alkyl, C₁-C₆ alkenyl, halogen, C₁-C₆ haloalkyl,trifluromethylsulfonyl, OR⁷, NR⁸R⁹, C₁-C₆ alkyl-OR⁷, C₁-C₆ alkyl-NR⁵R⁹,CONR⁸R⁹, COOR⁷, CN, SO₂NR⁸R⁹, SO₂R⁷, aryl, heteroaryl, heterocycloalkyl,3-, 4-, or 5-(2-oxo-1,3-oxazolidinyl), wherein any 2 adjacentsubstituents may be taken together to form a C₃-C₁₀ cycloalkyl ring, aC₃-C₁₀ cycloalkenyl ring or a heterocycloalkyl ring; or 3- or4-piperidinyl, 3-pyrrolidinyl, 3- or 4-tetrahydropyranyl,3-tetrahydrofuranyl, 3- or 4-tetrahydropyranyl, 3-tetrahydrofuranyl, 3-or 4-tetrahydrothiopyranyl, 3- or 4-(1,1-dioxo) tetrahydrothiopyranyl,1-azabicyclo[4.4.0]decyl, 8-azabicyclo[3.2.1]octanyl, norbornyl,quinuclidinyl, indolin-2-one-3-yl, 2-(methoximino)-perhydroazepin-6-yl,each optionally substituted with 1 to 5 substituents independentlyselected at each occurrence from R⁷, C₁-C₆ alkyl-OR⁷, C₁-C₆ alkyl-NR⁸R⁹,CONR⁸R⁹, CN, COOR⁷ SO₂NRWR⁹, and SO₂R⁷; R⁶ is selected from H, C₁-C₆alkyl, C₃-C₁₀ cycloalkyl, (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, C₂-C₄alkenyl, aryl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl each of which isoptionally substituted with 1 to 5 substituents independently fromhalogen, C₁-C₆ haloalkyl, OR¹³, NR⁸R⁹, C₁-C₆ alkyl-OR³, C₁-C₆alkyl-NR⁸R⁹, CONR⁸R⁹, COOR⁷, CN, SO₂NR⁸R⁹, and SO₂R⁷; or R⁶ and R²jointly form with the two nitrogens to which they are bound a C₂-C₅aminocarbocycle optionally substituted at each occurrence by R⁷; R⁷ isindependently selected at each occurrence from H, C₁-C₆ alkyl, C₃-C₁₀cycloalkyl, C₃-C₁₀ cycloalkenyl, (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, C₁-C₃haloalkyl, or heterocycloalkyl, C₁-C₈ alkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, C₁-C₈ alkanoyl, aroyl, heteroaroyl, aryl,heteroaryl, C₁-C₆ arylalkyl or C₁-C₆ heteroarylalkyl each optionallysubstituted with 1 to 5 substituents independently selected fromhalogen, C₁-C₆ haloalkyl, OR, NR⁸R⁹, C₁-C₆ alkyl-OR¹³, C₁-C₆alkyl-NR⁸R⁹, CONR⁸R⁹, COOR¹³, CN, SO₂NR⁸R⁹, and SO₂R¹³, with the provisothat when R⁷ is SO₂R¹³, R¹³ cannot be H; R⁸ and R⁹ are independentlyselected at each occurrence from H, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl,C₂-C₆ alkenyl, C₃-C₁₀ cycloalkenyl, C₂-C₆ alkynyl, heterocycloalkyl,C₁-C₈ alkanoyl, aroyl, heteroaroyl, aryl, heteroaryl, C₁-C₆ arylalkyl orC₁-C₆ heteroarylalkyl, or R⁸ and R⁹, taken together, can form a C₃-C₆aminocarbocycle or a C₂-C₅ aminoheterocycle each of which is optionallysubstituted with C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl,(C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, C₁-C₃ haloalkyl, or heterocycloalkyl,C₁-C₈ alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, C₁-C₈ alkanoyl,aroyl, heteroaroyl, aryl, heteroaryl, C₁-C₆ arylalkyl or C₁-C₆heteroarylalkyl; R¹¹ is selected from H, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl,(C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl; R¹² is selected from H, aryl,heteroaryl, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, (C₃-C₁₀ cycloalkyl) C₁-C₆alkyl, optionally substituted with OR⁷, NR⁸R⁹, C₃-C₆ aminocarbocycle, orC₂-C₅ aminoheterocycle; R¹³ is independently selected at each occurrencefrom H, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, with the proviso thatwhen R⁷ is SO₂R¹³, R¹³ cannot be H; and R¹⁴ is H, C₁-C₆ alkyl, C₃-C₁₀cycloalkyl, (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, C₂-C₄ alkenyl, C₂-C₄alkynyl, halo, or CN. or a pharmaceutically acceptable salt, hydrate orprodrug thereof.
 24. A compound in accordance with formula I

or a pharmaceutically acceptable salt, hydrate or prodrug thereofwherein: X is N or CR¹⁴; R¹ is selected from H, C₁-C₆ alkyl, C₃-C₆ycloalkyl, (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, cyano, halo, C₁-C₆ haloalkyl, OR⁷, C₁-C₆ alkyl-OR⁷; C₁-C₆cyanoalkyl, NR⁸R⁹, C₁-C₆ alkyl-NR⁸R⁹; R is H, C₁-C₆ alkyl, C₃-C₁₀cycloalkyl or (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, wherein each alkyl orcyclaoalkyl group may be optionally substituted with 1 to 3 R⁷a groups;R² may optionally join with R⁵ and the two and the 2 nitrogen atoms towhich they are bound to form a 6 to 10 membered heterocyclic ringoptionally substituted at each carbon with R⁷or R² and A may optionallyjoin to form a 3 to 8 membered heterocyclic ring optionally substitutedat each carbon with R^(7a); or or R¹ and B optionally join to form a 4to 10 membered heterocyclic ring optionally substituted at each carbonwith R⁷l or A represents an alkyl chain of 1, 2 or 3 carbon atoms whichis optionally mono- or di-substituted at each carbon with substituentsindependently selected from C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, (C₃-C₁₀cycloalkyl) C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cyano, halo,C₁-C₆ haloalkyl, OR⁷, C₁-C₆ alkyl-OR⁷; C_(1,)-C₆ cyanoalkyl, NR⁸R⁹,C₁-C₆ alkyl-NR⁸R⁹,or A and B jointly form a C₃-C₆ carbocycle, optionallysubstituted at each occurrence with R^(7a); B represents an alkyl chainof 1, 2 or 3 carbons atoms, which is optionally mono- or di-substitutedat each carbon with substituents independently selected from Brepresents an alkyl chain of 1,2 or 3 carbons atoms, which is optionallymono- or di-substituted at each carbon with substituents independentlyselected from C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, (C₃-C₁₀ cycloalkyl) C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cyano, halo, C₁-C₆ haloalkyl, OR⁷,C₁-C₆ alkyl-OR⁷; C₁-C₆ cyanoalkyl, NR⁸R⁹, and C₁-C₆ alkyl-NR⁸R⁹, or Band R⁵ may jointly form a 4 to 7 membered heterocyclic ring, which isoptionally substituted at each atom with R^(7a); R³ is selected from H,C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, cyano, halo, C₁-C₆ haloalkyl, OR⁷, C₁-C₆alkyl-OR⁷, C₁-C₆ cyanoalkyl, NR⁸R⁹, C₁-C₆ allyl-NR⁸R⁹; R⁴ is selectedfrom aryl or heteroaryl, each of which is substituted with 1 to 5substituents independently selected from C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl,C₃-C₁₀ cycloalkenyl, (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, C₁-C₆ alkenyl,C₁-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, trifluromethylsulfonyl, OR⁷,C₁-C₆ alkyl-OR⁷, NR⁸R⁹, C₁-C₆ alkyl-NR⁸R⁹, CONR⁸R⁹, C₁-C₆ alkyl-CONR⁸R⁹,COOR⁷, C₁-C₆ alkyl-COOR⁷, CN, C₁-C₆ alkyl-CN, SO₂NR⁸R⁹, SO₂R⁷, aryl,heteroaryl, heterocycloalkyl, 3-, 4-, or 5-(2-oxo-1,3-oxazolidinyl),C₂-C₄ alkynyl wherein at least one of the positions ortho or para to thepoint of attachment of the aryl or heteroaryl ring to the pyrazole issubstituted; R⁵ is selected from: C₁-C₆ alkyl, (C₃-C₁₀ cycloalkyl) C₁-C₆alkyl, each of which is substituted with 1 to 5 groups independentlyselected at each occurrence from C₁-C₆ alkyl, C₃-C₁₀, cycloalkyl, C₃-C₁₀cycloalkenyl, (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, C₂-C₆, alkenyl, halogen,C₁-C₆ haloalkyl, OR⁷, NR⁸R⁹, (with the proviso that when two OR⁷ orNR⁸R⁹ substituents are geminally located on the same carbon R⁷ is not Hand the geminally located OR⁷ or NR⁸R⁹ substitutuents can be takentogether to form a C₂-C₄ ketal, oxazoline, oxazolidine, imidazoline, orimidazolidine heterocycle), C₁-C₆ alkyl-OR⁷, C₁-C₆ alkyl-NR⁸R⁹, CONR⁸R⁹,COOR⁷, CN, oxo, hydroximino, C₁-C₆ alkoximino, SO₂NR⁸R⁹, SO₂R⁷,heterocycloalkyl, aryl, heteroaryl, where aryl or heteroaryl isoptionally substituted with 1 to 5 substituents independently selectedat each occurrence from C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀cycloalkenyl, (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, C₂-C₆ alkenyl, halogen,C₁-C₆ haloalkyl, trifluromethylsulfonyl, OR⁷, NR⁸R⁹, C₁-C₆ alkyl-OR₇,C₁-C₆ alkyl NR⁸R⁹, CONR⁸R⁹, COOR⁷, CN, SO₂NR⁸R⁹, SO₂R⁷, aryl,heteroaryl, heterocycloalkyl, 3-, 4-, or 5-(2-oxo-1,3-oxazolidinyl),with the proviso that 2 adjacent substituents can optionally formtogether a C₃-C₁₀, cycloalkyl ring, a C₃-C₁₀ cycloalkenyl ring or aheterocycloalkyl ring; with the proviso that C₁-C₆ alkyl group issubstituted with a C₁-C₆ alkyl group to give a C₇-C₁₀ alkyl groupAryl(C₁-C₆) alkyl, heteroaryl(C₁-C₆)alkyl, aryl(C₅-C₈)cycloalkyl, orheteroaryl(C₅-C₈)cycloalkyl, each of which is optionally substitutedwith 1 to 5 substituents independently selected at each occurrence fromC₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl, (C₃-C₁₀ cycloalkyl)C₁-C₆ alkyl, C₁-C₆ alkenyl, halogen, C₁-C₆ haloalkyl,trifluoromethylsulfonyl, OR⁷, NR⁸R⁹, C₁-C₆ alkyl-OR⁷, C₁-C₆ alkyl-NR⁸R⁹,CONR³R⁹, COOR⁷, CN, SO₂NR⁸R⁹, SO₂R⁷, aryl, heteroaryl, heterocycloalkyl,3-, 4-, or 5-(2-oxo-1,3-oxazolidinyl), wherein any 2 adjacentsubstituents may be take together to form a C₃-C₁₀ cycloalkyl ring, aC₃-C₁₀ cycloalkenyl ring or a heterocycloalkyl ring; C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₁₀ cycloalkenyl, or a 3 to 10 membered mono- orbicyclic heterocycle containing 1-3 O, S or N atoms, each of which isoptionally substituted with 1 to 6 substituents independently selectedfrom C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl, (C₃-C₁₀cycloalkyl) C₁-C₆ alkyl, C₂-C₆ alkenyl, halogen, C₁-C₆ haloalkyl, OR⁷,NR⁸R⁹, (with the proviso that when two OR⁷ or NR8R⁹ substituents aregeminally located on the same carbon R⁷ is not H and the geminallylocated OR⁷ or NR⁸R⁹ substitutuents can be taken together to form aC₂-C₄ ketal, oxazoline, oxazolidine, imidazoline, or imidazolidineheterocycle), C₁-C₆ alkyl-OR⁷, C₁-C₆ alkyl-NR⁸R⁹, CONR⁸R⁹, COOR⁷, CN,oxo, hydroximino, C₁-C₆ alkoximino, SO₂NR⁸R⁹, SO₂R⁷, COR⁷,heterocycloalkyl, aryl, C₁-C₆ alkylaryl, heteroaryl, C₁-C₆alkylheteroaryl where aryl or heteroaryl is optionally substituted with1 to 5 substituents independently selected at each occurrence from C₁-C₆alkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl, (C₃-C₁₀ cycloalkyl) C₁-C₆alkyl, C₂-C₆ alkenyl, halogen, C₁-C₆ haloalkyl, triflluromethylsulfonyl,OR⁷, NR⁸R⁹, C₁-C₆ alkyl-OR⁷, C₁-C₆ alkyl-NR⁸R⁹, CONR⁸R⁹, COOR⁷, CN,SO₂NR⁸R⁹, SO₂R⁷, aryl, heteroaryl, heterocycloalkyl, 3-, 4-, or5-(2-oxo-1,3-oxazolidinyl), with the proviso that 2 adjacentsubstituents can optionally form together a C₃-C₁₀ cycloalkyl ring, aC₃-C₁₀ cycloalkenyl ring or a heterocycloalkyl ring; or aryl orheteroaryl, optionally substituted with 1 to 5 substituentsindependently selected at each occurrence from halogen, C₁-C₆ alkyl,C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl, (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl,C₂-C₆ alkenyl, halogen, C₁-C₆ haloalkyl, trifluromethiylsulfonyl, OR⁷,NR⁸R⁹, C₁-C₆ alkyl-OR⁷, C₁-C₆ alkyl-NR⁸R⁹, CONR⁸R⁹, COOR⁷, CN, SO₂NR⁸R⁹,S02R⁷, aryl, heteroaryl, heterocycloalkyl, 3-, 4-, or5-(2-oxo-1,3-oxazolidinyl), wherein any 2 adjacent substituents may betaken together to form a C₃-C₁₀ cycloalkyl ring, a C₃-C₁₀ cycloalkenylring or a heterocycloalkyl ring; R⁶ is selected from H, C₁-C₆ alkyl,C₃-C₁₀ cycloalkyl, (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, C₂-C₄ alkenyl,aryl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl each of which is optionallysubstituted with 1 to 5 substituents independently from halogen, C₁-C₆haloalkyl, OR¹³, NR⁸R⁹, C₁-C₆ alkyl-OR³, C₁-C₆ alkyl-NR⁸R⁹, CONR⁸R⁹,COOR⁷, CN, SO₂NR⁸R⁹, and SO₂R⁷; R⁷ is independently selected at eachoccurrence from H, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl,(C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, C₁-C₃ haloalkyl, or heterocycloalkyl,aryl, heteroaryl, C₁-C₆ arylalkyl or C₁-C₆ heteroarylalkyl eachoptionally substituted with 1 to 5 substituents independently selectedfrom halogen, C₁-C₆ haloalkyl, OR¹³, NR⁸R⁹, C₁-C₆ alkyl-OR¹³, C₁-C₆alkyl-NR⁸R⁹, CONR⁸R⁹, COOR¹³, CN, SO₂NR⁸R⁹, and SO₂R¹³; R^(7a) isindependently selected at each occurrence from H, C₁-C₆ alkyl, C₃-C₁₀cycloalkyl, C₃-C₁₀ cycloalkenyl, (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, C₁-C₃haloalkyl, or heterocycloalkyl, C₁-C₈ alkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, C₁-C₈ alkanoyl, aroyl, heteroaroyl, aryl,heteroaryl, C₁-C₆ arylalkyl or C₁-C₆ heteroarylalkyl each optionallysubstituted with 1 to 5 substituents independently selected fromhalogen, C₁-C₆ haloalkyl, OR¹³, NR⁵R⁹, C₁-C₆ alkyl-OR¹³, C₁-C₆alkyl-NR⁸R⁹, CONR⁸R⁹, COOR¹³, CN, SO₂NR⁸R⁹, and SO₂R¹³, with the provisothat when R^(7a) is SO₂R¹³, R cannot be H; R⁸ and R⁹ are independentlyselected at each occurrence from H, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl,C₂-C₆alkenyl, C₃-C₁₀ cycloalkenyl, C₂-C₆ alkynyl, heterocycloalkyl, C₁-C₈alkanoyl, aroyl, heteroaroyl, aryl, heteroaryl, C₁-C₆ arylalkyl or C₁-C₆heteroarylalkyl, or R⁸ and R⁹ taken together, can form a C₃-C₆aminocarbocycle or a C₂-C₅ aminoheterocycle each of which isoptionallysubstituted with C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkenyl,(C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, C₁-C₃ haloalkyl, or heterocycloalkyl,C₁-C₈ alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, C₁-C₈ alkanoyl,aroyl, heteroaroyl, aryl, heteroaryl, C₁-C₆ arylalkyl or C₁-C₆heteroarylalkyl; R¹¹ is selected from H, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl,(C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl; R¹² is selected from H, aryl,heteroaryl, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, (C₃-C₁₀ cycloalkyl) C₁-C₆alkyl, optionally substituted with OR⁷, NR⁸R⁹, C₃-C₆ aminocarbocycle, orC₂-C₅ aminoheterocycle; R¹³ is independently selected at each occurrencefrom H, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, with the proviso thatwhen R⁷ is for SO₂R¹³, R¹³ cannot be H; and R¹⁴ is H, C₁-C₆ alkyl,C₃-C₁₀ cycloalkyl, (C₃-C₁₀ cycloalkyl) C₁-C₆ alkyl, C₂-C₄ alkenyl, C₂-C₄alkynyl, halo, or CN.
 25. A compound according to claim 24, wherein R¹⁴is H, C₁-C₄ alkyl, F or Cl.
 26. A Compound according to claim 25,wherein R¹⁴ is H, C₁-C₄ alkyl, (C₃-C₆ cycloalkyl) C₁-C₂ alkyl, where thealkyl and cycloalkyl groups are optionally substituted with 1-3fluorines. R³ is H, C₁-C₄ alkyl, (C₃-C₆ cycloalkyl) C₁-C₂ alkyl, wherethe alkyl and cycloalkyl groups are optionally substituted with 1-3fluorines. A is CH₂, optionally substituted with one or two of thefollowing: F, CF₃, or C₁-C₃ alkyl; B is a 1, 2 or 3 carbon chain,optionally substituted with one or two of the following: F, CF₃, orC₁-C₃ alkyl.
 27. A Compound according to claim 26, wherein R⁴ is phenyl,substituted with 2 or 3 substituents independently selected from C₁-C₃alkyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkenyl, (C₃-C₅ cycloakyl) C₁-C₂alkyl, C₂-C₆ alkenyl, F, Cl, C₁-C₂ fluorooalkyl, OR⁷, C₁-C₃ alkyl-OR⁷,NR⁸R⁹, C₁-C₆ alkyl-NR⁸R⁹, CONR⁸R⁹, C₁-C₃ alkyl-CONR⁸R⁹, COOR⁷, C₂-C₆alkynyl, wherein the phenyl ring is minimally 2,4 disubstituted.
 27. ACompound according to claim 26, wherein R₂ is H; R⁶ is H; R⁴ is phenyl,substituted with 2 or 3 substituents independently selected from C₁-C₃alkyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkenyl, C₂-C₄ alkenyl, F, Cl, CF₃,CHF₂, CH₂CF₃, OMe, OCF₃, OEt, OPr, OiPr, C₂-C₄ alkyl OH, C₂-C₆ alkynyl,wherein the phenyl ring is minimally 2,4 di-substituted.
 28. A Compoundaccording to claim 27, wherein A is CH₂; B is CH₂; B and R₅ form a 5 to7 membered heterocyclic ring, substituted on carbon with R^(7a). R^(7a)is independently selected at each occurrence from H, C₁-C₃ alkyl, C₃-C₆cycloalkyl, C₃-C₆ cycloalkenyl, (C₃-C₆ cycloalkyl) C₁-C₂ alkyl, C₁-C₂fluoroalkyl, heterocycloalkyl, C₁-C₄ alkanoyl, aroyl, heteroaroyl, aryl,heteroaryl, C₁-C₂ arylalkyl or C₁-C₂ heteroarylalkyl each optionallysubstituted with 1 to 3 substituents independently selected from F, Cl,CF₃, OR¹³, NR⁸R⁹, C₁-C₂ alkyl-OR¹³, C₁-C₂ alkyl-NR⁸R⁹, CONR⁸R⁹, COOR¹³,and CN; R⁸ is H, C₁-C₃ alkyl, CF₃ or CH₂CF₃. R⁹ is H or C₁-C₃ alkyl. R¹³is H, C₁-C₃ alkyl, CF₃ or CH₂CF₃.
 29. A Compound according to claim 27,wherein A is CH₂, optionally substituted with one or two of thefollowing: F, CF₃, or methyl, ethyl, isopropyl; B is CH₂, optionallysubstituted with one or two of the following: F, CF₃, methyl, ethyl, orIsopropyl.
 30. A Compound according to claim 29, wherein R⁵ is C₁-C₇,alkyl, C₃-C₆cycloalkyl, or C₃-C₆ cycloalkyl C₁-C₂ alkyl, substitutedwith F, CF₃, OR⁷ or NR⁸R⁹; A is CB₂, optionally substituted with methyl;B is CH₂, optionally substituted with methyl; X is N or CH.
 31. Acompound according to claim 30, wherein R⁷ is H, C₁-C₃ alkyl, CF₃ orCH₂CF₃; R⁸ is H, C₁-C₃ alkyl, CF₃ or CH₂CF₃, R⁹ is H or C₁-C₃ alkyl orNR⁸R⁹ taken together to form a pyrrolidine, piperidine or morpholinering.
 32. A Compound according to claim 29, wherein R⁵ is 3- or4-tetrahydropyranyl, 3-tetrahydrofluranyl, 3- or4-tetrahydrothiopyranyl, 3- or 4-cyclhexenyl, or 3-cyclopentenyl,optionally substituted with 1 or 2 substituents selected from C₁-C₃alkyl; A is CH₂, optionally substituted with methyl; B is CH₂ optionallysubstituted with methyl; and X is Nor CH.
 33. A Compound according toclaim 29, wherein R⁵ is 3- or 4-piperidinyl or 3-pyrrolidinyl,optionally substituted on 1 or 2 carbons with C₁-C₃ alkyl, and onesubstituent on nitrogen from H, C₁-C₆, alkyl, C₃-C₆ cycloalkyl, C₃-C₆cycloalkenyl, (C₃-C₆ cycloalkyl) C₁-C₂ alkyl, C₁-C₄ alkenyl, C₁-C₃fluoroalkyl, C₂-C₄ alkyl-OR⁷, C₂-C₄ alkyl-NR⁸R⁹, heterocycloalkyl,CO-C₁-C₄ alkyl, aryl, C₁-C₃, alkylaryl, heteroaryl, C₁-C₃alkylheteroaryl where aryl or heteroaryl is optionally substituted with1 to 3 substituents independently selected at each occurrence from C₁-C₃alkyl F, Cl, C₁-C₂ fluoroalkyl, OR⁷, NR⁸R⁹, C₁-C₂ all-OR⁷, C₁-C₂alkyl-NR⁸R⁹, CONR⁸R⁹, COOR⁷, CN, SO₂NR⁸R⁹, SO₂R⁷, aryl, heteroaryl,heterocycloalkyl, 3 -, 4-, or 5 -(2-oxo-1,3-oxazolidinyl).
 34. ACompound according to claim 33, wherein R⁵ is 3- or 4-piperidinyl or3-pyrrolidinyl, optionally substituted on nitrogen with H, C₁-C₃ alkyl,CH₂CF₃, acetyl, pyridyl, benzyl, methylenepyridyl, pyrimidinyl, orpyrazinyl, where the aryl or heteroaryl group is optionally substitutedwith 1 to 2 substituents independently selected at each occurrence fromC₁-C₃, alkyl, F, Cl, CF₃, OR, NR⁸R⁹. R⁷ is H, C₁-C₂, alkyl, CF₃ orCH₂CF₃. R⁸ is H, C₁-C₂ alkyl, CF₃ or CH₂CF₃. R⁹ is H or C₁-C₂ alkyl. Ais CH₂, optionally substituted methyl; B is CH₂, optionally substitutedwith methyl; X is N or CH.
 35. A compound according to claim 29, whereinR⁵ is C₁-C₂ arylalkyl, C₁-C₂ heteroarylalkyl, C₃-C₄ arylcycloalkyl, orC₃-C₄ heteroarylcycloalkyl, where aryl is phenyl or naphthyl, andheteroaryl is 2-, 3-, or 4-pyridyl, 2-, 4- or 5 pyrimidinyl, triazinyl,1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, isoxazolyl, indolyl,pyrazolyl, quinolyl, isoquinolyl, 2-, 4-, or 5-thiazolyl,benzothiadiazolyl, 1-, 3- or 4 pyrazolyl, 1-, 3- or 4-triazolyl,2-triazinyl, 2-pyr, zinyl, 2-, or 3-furanyl, 2-, or 3-thienyl, 2-, or3-benzothienyl, or 1-, 2- or 5-tetrazolyl, each of which is optionallysubstituted with 1 to 3 substituents independently selected at eachoccurrence from C₁-C₃ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkenyl,(C₃-C₆ cycloalkyl) C₁-C₂ alkyl, C₁-C₆ alkenyl, F, Cl, C₁-C₂ fluoroalkyl,OR⁷, NRR⁹, C₁-C₂ alkyl-OR⁷, C₁-C₂ alkyl-NR⁸R⁹ or CN.
 36. A compoundaccording to claim 35, wherein R⁵ is phenethyl, pyridinylethyl, or2-tetrahydonaphthylenyl, each of which is optionally substituted with 1to 2 substituents independently selected at each occurrence from C₁-C₂alkyl, F, Cl, CF₃, OR⁷, NR⁸R⁹. R⁷ is H, C₁-C₂ alkyl, CF₃ or CH₂CF₃. R⁸is H, C₁-C₂ alkyl, CF₃ or CH₂CF₃. R⁹ is H or C₁-C₂ alkyl. A is CH,optionally substituted with methyl; B is CH₂, optionally substitutedwith methyl; X is N or CH.
 37. A compound according to claim 28, wherethe structure is[3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-(6-methyl-piperidin-2-ylmethyl)-amine.
 38. Acompound according to claim 31, where the compound is selected frommthegroup consisting of:2-{2-[3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-ylamino]-ethylamino}-butan-1-ol;N-{2-[3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-ylamino]-ethyl}-N′-methyl-cyclohexane-1,4-diamine;N-{2-[3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-ylamino]-ethyl}-N′-ethyl-cyclohexane-1,4-diamine;N-[3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N′-(4-morpholin-4-yl-cyclohexyl)-ethane-1,2-diamine;4-{2-[3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-ylamino]-ethylaminol}-cyclohexanol;3-{2-[3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-ylamino]-ethylamino}-propane-1,2-diol;N-{2-[3(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-ylamino]-ethyl}-N′-isobutyl-cyclohexane-1,4-diamine;N-{2-[3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo[l1,5-a]pyrimidin-7-ylamino]-ethyl}-N′-isobutyl-cyclohexane-1,4-diamine;4-{2-[3-(2,6-dichloro-4-ethoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-ylamino]-1-methyl-ethylamino}-cyclohexanol;2-{2-[3-(2,6-dichloro-4-ethoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-ylamino]-ethylamino}-cyclohexanol;N-[3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazo to[1,5-a]pyrimidin-7-yl]-N′-(4,4,4-trifluoro-butyl)-ethane-1,2-diamine;N-[3-(2,6-dichloro-4-ethoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N′-(2,2,2-trifluoro-ethyl)-ethane-1,2-diamine;N-[3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N′-(2-trifluoromethyl-cyclohexyl)-ethane-1,2-diamine;N-[3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo [1,5-a]pyrimidin-7-yl]-N′-(4-trifluoromethyl-cyclohexyl)-ethane 1,2-diamine;N-[3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N′-(2,2-difluoro-ethyl)-ethane-1,2-diamine;N-[3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N′-(2-fluoro-1-methyl-ethyl)-ethane-1,2-diamine;N-[3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazoto[1,5-a]pyrimidin-7-yl]-N′-(2-fluoro-cyclohexyl)-ethane-1,2-diamine. 39.A compound of claim 32, where the compound is selected from the groupconsisting ofN-[3-(2,6-dichloro-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N′-(tetrahydro-pyran-4-yl)-ethane-1,2-diamine;N-[3-(2,4-dichloro-6-methoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N′-(tetrahydro-pyran-4-yl)-ethane-1,2-diamine;N-[3-(2,6-dichlork)-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N′-(tetrahydro-pyran-4-yl)-ethane-1,2-diamine;N1-[3-(2,6-Dichloro-phenyl)-2,5-dimethyl-pyrazo to[1,5-a]pyrimidin-7-yl]-N2&-(tetrahydro-pyran -4-yl)-propane-1,2-diamine;N-[3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N-(2-methyl-tetrahydro-ftiran-3-yl)-ethane-1,2-diamine;N-[3-(2,6-dichloro-4-ethoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N′-(tetrahydro-pyran-4-yl)-ethane-1,2-diamine;3,5-dichloro-4-{2,5-dimethyl-7-[2-(tetrahydro-pyran-4-ylamino)-ethylamino]-pyrazolo[1,5-a]pyrimidin-3-yl}-benzonitrile;N-[3-(2,6-dichloro-4-propoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N′-(tetrahydro-pyran-4-yl)-ethane-1,2-diamine;2-(3,5-dichloro-4-(2,5-dimethyl-7-[2-(tetrahydro-pyran-4-ylamino)-ethylamino]-pyrazolo[1,5-a]pyrimidin-3-yl} -phenyl)-propan -2-ol;N-[3-(2,6-dichloro-4-cyclopent-1-enyl-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N-(tetrahydro-pyran-4-yl)-ethane-1,2-diamine;N-[8-(2,6-dichloro-4-ethoxy-phenyl)-2,7-dimethyl-pyrazolo [1,5-a][1,3,5]triazin-4-yl]-N′-(tetrahydro-pyran-4-yl)-ethane-1,2-diamine;(3.5-dichloro-4-(2,5-dimethyl-7-[2-(tetrahydro-pyran-4-ylamino)-ethylamino]-pyrazolo[1,5-a]pyrimidin-3-yl}-phenyl)-methanol;N-[3-(2,6-dichloro-4-ethoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N-(2-methyl-tetrahydro-furan-3-yl)-ethane-1,2-diamine;N-[5-tert-butyl-3-(2,6-dichloro-4-methoxy-phenyl) -2-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N′-(tetrahydro-pyran-4-yl)-ethane-1,2-diamine;N-[3-(2,6-dichloro-4-ethoxy-phenyl)-5-ethyl-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N-(tetrahydro-pyran-4-yl)-ethane-1,2-diamine;N-cyclohex-3-enyl-N′-[3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-ethane-1,2-diamine;N-cyclohex-3-enyl-N′-[8-(2,6-dichloro-4-ethoxy-phenyl)-2,7-dimethyl-pyrazolo[1,5-a][1,3,5]triazin-4-yl]-ethane-1,2-diamine;N-cyclopent-3-enyl-N′-[3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo [1,5-a]pyrimidin-7-yl]-ethane-1,2-diamine.
 40. Acompound of claim 34 where the structure is selected from the groupconsisting of N-[3-(2,6-dichloro-phenyl)-2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-yl]-N′-(1-ethyl-piperidin-5-a]pyrimidin-7-yl]-N′-(2,2,6,6-tetramethyl-piperidin-4-yl)-ethane-1,2diamine;N-[3-(2,6-dichloro-phenyl)-2,5-dimethyi-pyrazolo[1,5-a]pyrimidin-7-yl]-N′-19piperidin-4-yl-ethane-1,2-diamine;N-[3-(2,6-dichloro-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N-(1-ethyl-piperidin-3-yl)-ethane-1,2-diamine;N-(1benzyl-pyrrolidin-3-yl)-N′-[3-(2,6-dichloro-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-ethane-1,2-diamine;N-[3-(2,6-dichloro-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N-pyrimidin-2-yl-ethane-1,2-diamine;N-(1 -benzylpiperidin-4-yl)-N-[3-(2,4-dichloro-6-methoxy-phenyl)-2,5-dimethyl-pyrazolo [1,5-a]pyrimidin-7-yl]-ethane-1,2-diamine; N-(1-benzyl-piperidin-4-yl)-N-[3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-ethane-1,2-diamine;N-[3(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N′-(1′-methyl-piperidin-4-yl)-ethane-1,2-diamine;N-[3-(2,6-dichloro-4-methoxy-phenyl)-2,5 dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N-(1-ethyl-piperidin-4-yl)-ethane-1,2-di amine;N-[3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N′-(1 -isopropyl-piperidin-4-yl)-ethane-1,2-diamine;N-[3-(2,6-dichloro-4-methoxy-phenyl)2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N′-(2,2,6,6-tetramethyl-piperidin-4-yl)ethane-1,2-diamine;N-[3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N′-(1-ethyl-piperidin-3-yl)-ethane-1,2-diamine;N-[3-(2,6-dichloro-4methoxy-phenyl)-2,5-dimethyl-pyrazo to [1,5-a]pyrimidin-7-yl]-N′-piperidin-4-yl-ethanel, 2-diamine;N²(1-Benzyl-piperidin-4-yl)-N′-[3-(2,6-dichloro-phenyl)-2,5-dimethyl-pyrazolo[1,5-ajpyrimidin-7-yl]-propane-1,2-diamine;N-[3-(2,6-Dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N′-(1-pyridin-3-ylmethyl-piperidin-4-yl)-ethane-1,2-diamine;N-[3-(2,6-Dichloro-4-methoxyphenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N′-(1-pyridin-4-ylmethyl-piperidin4-yl)-ethane-1,2-diamine;3,5-Dichloro-4-12,5-dimethyl-7-[2-(1-phenyl-pyrrolidin-3-ylamino)-ethylamino]-pyrazolo[1 ,5-a]pyrimidin-3-yl]-phenol;N-[3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N′-(1-pyridin-2-ylmethyl-piperidin-4-yl)-ethane-1,2-diamine;3,5-dichloro-4-(2,5-dimethyl-7-[2-(1-pyrimidin-2-yl-piperidin-4-ylamino)-ethylamino]-pyrazolo[1,5-a]pyrimidin-3-yl }-benzonitrile;N-[3-(2,6-dichloro-4-ethoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5a]pyrimidin-7-yl]-N′-(1-pyrimidin-2-yl-piperidin-4-yl)-ethane-1,2-diamine;N-[3-(2,6dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N′-(1-pyrimidin-2-yl-piperidin-4-yl)-ethane-1,2-diamine;N-(1-benzyl-piperidin-4-yl)-N′-[3(2,6-dichloro-4-ethoxy-phenyl)-2,5-dimethyl-pyrazolo1,5-a]pyrimidin-7-yl]-ethane-1,2-diamine;N-[3-(2,6-dichloro-phenyl)-5-ethyl-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N′-(1-pyrimidin-2-yl-piperidin-4-yl)-ethane-1,2-diamine;N-[3-(2,6-dichloro-phenyl)-5isopropyl-2-methyl-pyrazoto[1,5-a]pyrimidin-7-yl]-N-(1-pyrimidin-2-yl-piperidin-4-yl)ethane-1,2-diamine;N-[3-(2,4-dichloro-phenyl)-5-isopropyl-2-methyl-pyrazolo[1,5a]pyrimidin-7-yl]-N′-(1 -pyrimidin-2-yl-piperidin-4-yl)-ethane-1,2-diamine;N′-[3-(2,6-dichloro-4-ethoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N²-(1-pyrimidin -2-yl-piperidin-4-yl)-propane-1,2-diamine;N′-[3-(2,6-dichloro-4-methoxy-phenyl)-5isopropyl-2-methyl-pyrazoto[1,5-a]pyrimidin-7-yl]-N²-(1-pyrimidin-2-yl-piperidin-4-yl)propane-1,2-diamine;N-[3-(2,6-dichloro-4-methoxy-phenyl)-5-ethyl-2-methylpyrazoto[1,5-a]pyrimidin-7-yl]-N′-(1-pyrimidin-2-yl-piperidin-4-yl)-ethane-1,2-diamine;N′-[3-(2,6-dichloro-4-methoxy-phenyl)-2-methyl-5-propyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N²-(1-pyrimidin-2-yl-piperidin-4-yl)-propane-1,2-diamine;N′-[3-(2,6-dichloro-4methoxy-phenyl)-5-ethyl-2-methyl-pyrazoto[1,5-a]pyrimidin-7-yl]-N²-(1-pyrimidin-2-ylpiperidin-4-yl)-propane-1,2-diamine;N-[3-(2,6-dichloro-phenyl)-2-methyl-5-propylpyrazoto[1,5-a]pyrimidin-7-yl]-N′-(1-pyrimidin-2-yl-piperidin-4-yl)-ethane-1,2-diamine;N-[3-(2,6-dichloro-phenyl)-2-methyl-5-propyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N²-(1-pyrimidin-2-yl-piperidin-4-yl)-propane-1,2-diamine;N′-[3-(2,6-dichloro-phenyl)-5-ethyl2-methyl-pyrazolo[-1,5-a]pyrimidin-7-yl]-N²-(1-pyrimidin-2-yl-piperidin-4-yl)-propanel,2-diamine;N-[5-ethyl-2-methyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-N′-(]-pyrimidin-2-yl-piperidin-4-yl)-ethane-1,2-diamine;N′-[5-ethyl-2-methyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-N²-(1-pyrimidin-2-yl-piperidin-4-yl)-propane-1,2-diamine;N-[3-(2,6dichloro-4-ethynyl-phenyl)-2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-yl]-N-(1-pyrimidin-2-yl-piperidin-4-yl)-ethane-1,2-diamine;N-[2-methyl-5 -propyl-3 -(2,4,6-trimethyl-phenyl)-pyrazo to[1,5-a]pyrimidin-7-yl]-N′-(1pyrimidin-2-yl-piperidin-4-yl)-ethane-1,2-diamine;N′-[2,5-dimethyl-3-(2,4,6-trimethylphenyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-N′-(-pyrimidin-2-yl-piperidin-4-yl)-ethane-1,2-diamine;N′-[3-(2,6-Dimethyl-phenyl)-5-ethyl-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N′-(1-pyrimidin-2-yl-piperidin-4-yl)-propane-1,2-diamine; N-[3-(2,6-dimethyl-phenyl) -2-methyl-5-propyl-pyrazolo [ 1,5-a]pyrimidin-7-yl]-N′-(1-pyrimidin-2-yl-piperidin-4-yl)-ethane-1,2-diamine;N′-[3-(2,6-Dimethyl-phenyl)-2-methyl-5-propyl-pyrazolo[1,5-a]pyrimidin-7-yl]-NZ-(1-pyrimidin-2-yl-piperidin-4-yl)-propane-1,2-diamine;N′-[3-(2,6dimethyl-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N²-(1-pyrimidin-2-ylpiperidin-4-yl)-propane-1,2-diamine;N-[3-(2,4-dimethyl-phenyl)-5-ethyl-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N-(1-pyrimidin-2-yl-piperidin-4-yl)-ethane-1,2-diamine;N-[3-(2,4-dimethyl-phenyl)-2-methyl-5-propyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N′-(1-pyrimidin-2-yl-piperidin-4-yl)-ethane-1,2-diamine; and1-[4-(1{[3-(2,6-dichloro-4-methoxyphenyl)-2,5-dimethyl-pyrazolo [1,5-a]pyrimidin-7-ylamino ]-methyl ]-propylamino)piperidin-1-yl]-ethanone. 41 A compound of claim 37 wherethe structure is selected from the group consisting of N-[2,5-dimethyl-3-(2,4,6-trimethylphenyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-N-[2-(4-methoxy-phenyl)-ethyl]-ethane-1,2diamine;N-[3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N′-[2-(4-methoxy-phenyl)-ethyl]-ethane-1,2-diaamine;N-[3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N′-[2-(3-ethoxy-4-methoxy-phenyl)-ethyl]-ethane-1,2-diamine;N-[3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N′-[2-(4-ethoxy-3-methoxy-phenyl)-ethyl]ethane-1,2-diamine;N-[3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo[1,a]pyrimidin-7-yl]-N′-(1,2,3,4-tetrahydro-naphthalen-2-yl)-ethane-1,2-diamine;N-[3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N′-(2-pyridin-2-yl-ethyl)-ethane-1,2-diamine;N-[3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N′-(2-pyridin-3-yl-ethyl)-ethane-1,2-diamine;and N-[3-(2,6-dichloro-4-methoxy-phenyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidin-7-yl]-N′-(2-pyridin4-yl-ethyl)-ethane-1,2-diamine. 42.A method of treating obesity comprising administering to a mammal inneed of such treatment a therapeutically effective amount of a compoundof claim 23 or 24 or a prodrug thereof or a pharmaceutically acceptablesalt of said compound or of said prodrug.
 43. A method as recited inclaim 42 wherein the amount of saod compound administered is about 0.01mg/kg/day to about 50 mg/kg/day.
 44. A method as recited in claim 42wherein the mammal is female or male human.
 45. A pharmaceuticalcomposition which comprises a therapeutically effective amount ofcompound of claim 24 or a prodrug thereof or a pharmaceuticallyacceptable salt of said compound or of said prodrug and apharmaceutically acceptable carrier, vehicle or diluent.
 46. Apharmaceutical composition for the treatment of obesity which comprisesa therapeutically effective amount of compound of claim 24 or a prodrugthereof or a pharmaceutically acceptable salt of said compound or ofsaid prodrug and a pharmaceutically acceptable carrier, vehicle ordiluent.
 47. A pharmaceutical combination composition comprising atherapeutically effective amount of a composition comprising: (a) firstcompound, said first compound being a compound of claim 24, a prodrugthereof, or a pharmaceutically acceptable salt of said compound or ofsaid prodrug; and (b) a second compound, said second compound being agonist, a thyromimetic, an eating behavior modifying agent or a NPYantagonist; and a pharmaceutical carrier, vehicle, diluent.
 48. A methodof treating obesity comprising administering to a mammal in need of suchtreatment: (a) first compound, said first compound being a compound ofclaim 24, a prodrug thereof, or a pharmaceutically acceptable salt ofsaid compound or of said prodrug; and (b) a second compound, said secondcompound being a β₃ agonist, a thyromimetic, an eating behaviormodifying agent or a NPY antagonist; and a pharmaceutical carrier,vehicle, diluent; (and (c) wherein the amounts of the first and secondcompounds result in a therapeutic effect.
 49. A kit comprising: (a)first compound, said first compound being a compound of claim 24 or 25,a prodrng thereof, or a pharmaceutically acceptable salt of saidcompound or of said prodrug; (b) a second compound, said second compoundbeing a 3 agonist, a thyromimetic, an eating behavior modifying agent ora NPY antagonist; and a pharmaceutical carrier, vehicle, diluent; and(c) means for containing said first and second unit dosage forms whereinthe amounts of the first and second compounds result in a therapeuticeffect,
 50. A pharmaceutical combination composition comprising atherapeutically effective amount of a composition comprising (a) firstcompound, said first compound being a compound of claim 23 or 24, aprodrug thereof, or a pharmaceutically acceptable salt of said compoundor of said prodrug; (b) a second compound, said second compound being analdose reductase inhibitor, a glycogen phosphorylase inhibitor, asorbitol dehydrogenase N inhibitor, insulin metformin, acarbose, athiazolidinedione, a glitazone, rezulin, trogitalazone, a sulfonylurea,glipazide, glyburide, or chlorpropamide; (c) a pharmaceutical carrier,vehicle, or diluent.
 51. A pharmaceutical composition according to claim24 for the treatment of disorders or disease states caused by eatingdisorders, of obesity, bulimia nervosa, diabetes, dislipidemia,hypertension, memory loss, epileptic seizures, migraine, sleepdisorders, pain, sexual/reproductive disorders, depression, anxiety,cerebral hemorrhage, shock, congestive heart failure, nasal congestionor diarrhea. 52 A method of selectively inhibiting binding of NPY,receptors, which comprises contacting a compound of claim 1 withneuronal cells, wherein the compound is present in an amount effectiveto produce a concentration sufficient to selectively inhibit binding ofNPY peptides to NPY₁ receptors in vitro.